A phase I study of the combination of atezolizumab, tiragolumab, and stereotactic body radiation therapy in patients with metastatic multiorgan cancer.

BACKGROUND: Immunotherapy targeting the PD-1/PD-L1 pathway is a standard of care in a number of metastatic malignancies, but less than a fifth of patients are expected to respond to ICIs (Immune Checkpoint Inhibitors). In a clinical trial, combining the anti-TIGIT (T cell immunoreceptor with Ig and ITIM domains) Mab (monoclonal antibody) tiragolumab with atezolizumab improved outcomes in non-small cell lung cancer. In preclinical models, SBRT (Stereotactic Body Radiation Therapy) could increase expression levels of the inhibitory co-receptors TIGIT and PD-L1. We aim to assess the combination of tiragolumab with atezolizumab and SBRT in metastatic, previously treated by ICIs, non-small cell lung cancer, head and neck cancer, bladder cancer, and renal cell cancer. METHODS: This phase I study (ClinicalTrials.gov NCT05259319) will assess the efficacy and safety of the combination of atezolizumab with tiragolumab and stereotactic body radiation therapy in patients with histologically proven metastatic non-small cell lung cancer, renal cell cancer, bladder cancer, and head and neck cancer previously treated. First part: 2 different schedules of SBRT in association with a fixed dose of atezolizumab and tiragolumab will be investigated only with metastatic non-small cell lung cancer patients (cohort 1). The expansion cohorts phase will be a multicentric, open-label study at the recommended scheme of administration and enroll additional patients with metastatic bladder cancer, renal cell cancer, and head and neck cancer (cohort 2, 3 and 4). Patients will be treated until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment, or patient refusal in the absence of progression or intolerance. The primary endpoint of the first phase is the safety of the combination in a sequential or concomitant scheme and to determine the expansion cohorts phase recommended scheme of administration. The primary endpoint of phase II is to evaluate the efficacy of tiragolumab + atezolizumab + SBRT in terms of 6-month PFS (Progression-Free Survival). Ancillary analyses will be performed with peripheral and intratumoral immune biomarker assessments. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov: NCT05259319, since February 28th, 2022.

Cisplatin-based chemoradiation decreases telomerase-specific CD4 TH1 response but increases immune suppressive cells in peripheral blood.

BACKGROUND: The synergistic effect of chemoradiation (CRT) has been previously demonstrated in several cancer types. Here, we investigated the systemic immune effects of CRT in patients with lung or head and neck cancer. MATERIALS AND METHODS: Peripheral blood mononuclear cells were collected at baseline and 1 month after treatment from blood samples of 29 patients treated with cisplatin-based chemoradiotherapy for lung or head and neck cancer. Circulating anti-tumor Th1 response was assessed by the ELISpot assay using a mixture of human leucocyte antigen (HLA) class II restricted peptides derived from telomerase (TERT). Phenotyping of circulating immunosuppressive cells (Treg and MDSC) was performed by flow cytometry. RESULTS: A significant increase of circulating Treg was observed in 60% of patients after CRT The mean rate of Treg was 3.1% versus 4.9% at baseline and after CRT respectively, p = 0.0015). However, there was a no significant increase of MDSC rate after CRT. In contrast, a decrease of tumor-specific Th1 response was documented in 7 out of 10 evaluated patients. We found high frequency of pre-existing tumor-specific Th1 response among patients with objective response after CRT compared to non-responders. CONCLUSION: Cisplatin-based CRT promotes expansion of Treg and decrease of circulating anti-tumor Th1 response in peripheral blood. The balance towards a sustained specific anti-tumor T-cell response appears to be associated with response to CRT.

Clinical and dosimetric study of radiotherapy for glioblastoma: three-dimensional conformal radiotherapy versus intensity-modulated radiotherapy.

BACKGROUND AND PURPOSE: We aimed to compare three-dimensional conformal radiotherapy (3D-CRT) with intensity-modulated radiotherapy (IMRT) for the treatment of glioblastoma. MATERIALS AND METHODS: Retrospective study of 220 patients with glioblastoma, treated with 3D-CRT or IMRT, with or without surgery. Dosimetric parameters as well as clinical and survival data for the two techniques were analyzed and compared. RESULTS: The median conformity index was 1.53 (range 0-2.69) for 3D-CRT and 1.25 (range 0.97-2.01) for IMRT, p < 10-4. The median homogeneity index was 0.10 (range 0.03-0.32) for 3D-CRT and 0.07 (range 0.03-0.18) for IMRT, p < 10-4. There were significantly fewer acute grade 1 and 2 neurological toxicities in the IMRT group especially for edema (1.3 versus 12.4%, p = 0.017), concentration disorders (6.6 versus 19.9%, p = 0.003) and consciousness disorders (2.6 versus 13.2%, p = 0.002) although IMRT patients had a significantly worse pre-treatment neurological status than 3D-CRT patients. Median survival was 16.0 months (range 11.9-17.8) for IMRT and 13.4 months (range 11.7-15.7) for 3D-CRT patients (p = 0.542). CONCLUSION: IMRT improved target conformity and reduced neurological toxicities for patients with glioblastomas.

A comparison of target volumes drawn on arterial and venous phase scans during radiation therapy planning for patients with pancreatic cancer: the PANCRINJ study.

BACKGROUND: The planification of radiation therapy (RT) for pancreatic cancer (PC) requires a dosimetric computed tomography (CT) scan to define the gross tumor volume (GTV). The main objective of this study was to compare the inter-observer variability in RT planning between the arterial and the venous phases following intravenous contrast. METHODS: PANCRINJ was a prospective monocentric study that included twenty patients with non-metastatic PC. Patients underwent a pre-therapeutic CT scan at the arterial and venous phases. The delineation of the GTV was performed by one radiologist (gold standard) and two senior radiation oncologists (operators). The primary objective was to compare the Jaccard conformity index (JCI) for the GTVs computed between the GS (gold standard) and the operators between the arterial and the venous phases with a Wilcoxon signed rank test for paired samples. The secondary endpoints were the geographical miss index (GMI), the kappa index, the intra-operator variability, and the dose-volume histograms between the arterial and venous phases. RESULTS: The median JCI for the arterial and venous phases were 0.50 (range, 0.17-0.64) and 0.41 (range, 0.23-0.61) (p = 0.10) respectively. The median GS-GTV was statistically significantly smaller compared to the operators at the arterial (p < 0.0001) and venous phases (p < 0.001), respectively. The GMI were low with few tumors missed for all patients with a median GMI of 0.07 (range, 0-0.79) and 0.05 (range, 0-0.39) at the arterial and venous phases, respectively (p = 0.15). There was a moderate agreement between the radiation oncologists with a median kappa index of 0.52 (range 0.38-0.57) on the arterial phase, and 0.52 (range 0.36-0.57) on the venous phase (p = 0.08). The intra-observer variability for GTV delineation was lower at the venous phase than at the arterial phase for the two operators. There was no significant difference between the arterial and the venous phases regarding the dose-volume histogram for the operators. CONCLUSIONS: Our results showed inter- and intra-observer variability in delineating GTV for PC without significant differences between the arterial and the venous phases. The use of both phases should be encouraged. Our findings suggest the need to provide training for radiation oncologists in pancreatic imaging and to collaborate within a multidisciplinary team.

Deep learning application for abdominal organs segmentation on 0.35 T MR-Linac images.

Introduction: Linear accelerator (linac) incorporating a magnetic resonance (MR) imaging device providing enhanced soft tissue contrast is particularly suited for abdominal radiation therapy. In particular, accurate segmentation for abdominal tumors and organs at risk (OARs) required for the treatment planning is becoming possible. Currently, this segmentation is performed manually by radiation oncologists. This process is very time consuming and subject to inter and intra operator variabilities. In this work, deep learning based automatic segmentation solutions were investigated for abdominal OARs on 0.35 T MR-images. Methods: One hundred and twenty one sets of abdominal MR images and their corresponding ground truth segmentations were collected and used for this work. The OARs of interest included the liver, the kidneys, the spinal cord, the stomach and the duodenum. Several UNet based models have been trained in 2D (the Classical UNet, the ResAttention UNet, the EfficientNet UNet, and the nnUNet). The best model was then trained with a 3D strategy in order to investigate possible improvements. Geometrical metrics such as Dice Similarity Coefficient (DSC), Intersection over Union (IoU), Hausdorff Distance (HD) and analysis of the calculated volumes (thanks to Bland-Altman plot) were performed to evaluate the results. Results: The nnUNet trained in 3D mode achieved the best performance, with DSC scores for the liver, the kidneys, the spinal cord, the stomach, and the duodenum of 0.96 ± 0.01, 0.91 ± 0.02, 0.91 ± 0.01, 0.83 ± 0.10, and 0.69 ± 0.15, respectively. The matching IoU scores were 0.92 ± 0.01, 0.84 ± 0.04, 0.84 ± 0.02, 0.54 ± 0.16 and 0.72 ± 0.13. The corresponding HD scores were 13.0 ± 6.0 mm, 16.0 ± 6.6 mm, 3.3 ± 0.7 mm, 35.0 ± 33.0 mm, and 42.0 ± 24.0 mm. The analysis of the calculated volumes followed the same behavior. Discussion: Although the segmentation results for the duodenum were not optimal, these findings imply a potential clinical application of the 3D nnUNet model for the segmentation of abdominal OARs for images from 0.35 T MR-Linac.

Evaluation of the quality of the information received during head and neck cancer announcement: Prospective two-center study.

BACKGROUND: Providing patient with cancer with appropriate information following the disclosure of a cancer diagnosis has multiple benefits. The objective was to evaluate the quality of the information received during an announcement for head and neck cancer and to determine predictive factors. METHODS: We conducted a prospective two-center study using self-questionnaires to assess the patient's perception of the quality of the announcement. RESULTS: Satisfaction scores on the information provided about the overall disease were 7.7/10. The main positive predictors of quality were a satisfactory consultation setting (P = .004), assessment of pain by a physician (P = .04), physician availability (P = .003), accurate information about tumor stage, quality of information regarding the type (P < .0001) and purpose (P = .001) of treatment and its side effects (P = .006), and the interview with the oncology nurse coordinator (P < .05). CONCLUSIONS: Patients who received the announcement of head and neck cancer perceived the information received during the pretherapeutic period as satisfactory.

Impact of waiting time on nodal staging in head and neck squamous-cell carcinoma treated with radical intensity modulated radiotherapy.

BACKGROUND AND PURPOSE: To evaluate the influence of delays for radiotherapy on survival, recurrence and upstaging for head and neck squamous-cell carcinoma (HNSCC) with no nodal involvement treated with intensity modulated radiotherapy (IMRT). MATERIAL AND METHODS: This retrospective study included 63 consecutive patients with HNSCC located in the pharynx and larynx and treated with exclusive IMRT with or without chemotherapy. Survival, loco-regional or distant failure and upstaging were analyzed according to the waiting time. RESULTS: Mean waiting time for treatment was 62.5 days for the hypopharynx subgroup (range = 37-102), 63 days for the larynx subgroup (range = 19-128) and 58.5 days for the oropharynx subgroup (range = 29-99) (p = 0.725). Nine patients (14%) experienced upstaging. Loco-regional or distant failure occurred in 18 patients. Beyond a delay of 50 days, 19% of patients had local failure, 17% nodal recurrence and 11% distant failure. Within a delay of 50 days, no nodal or distant failure was observed and only 1 patient experienced local recurrence. Upstaging and overall survival were not significantly affected by an increased waiting time. CONCLUSION: For N0 patients treated with IMRT for HNSCC, waiting time around 50 days after the diagnosis was not significantly associated with an excessive risk of upstaging or recurrence.

Mapping of failures after radiochemotherapy in patients with non-metastatic esophageal cancer: A posteriori analysis of the dose distribution in the sites of loco-regional relapse.

BACKGROUND AND PURPOSE: We aimed to evaluate the patterns of loco-regional failure (LRF) after exclusive chemoradiotherapy (eCRT) for esophageal cancer with respect to planned dose and/or the incidental (unplanned) dose outside target volumes. MATERIALS AND METHODS: Co-image registration of CT or (18)F-FDG PET-CT at the time of failure (tf) and at the time of CRT (t0) was performed in 34 patients with LRF. Dosimetric parameters with regard to local failure (LF), nodal failure (NF) and involved nodal stations (NS) were derived. RESULTS: Twenty-two patients (64.7%) had LF, the majority of which (95.5%) were located at the epicenter of the GTV of the primary tumor. The mean doses recalculated to the NS at tf were more likely to be lower than the planned dose delivered to the PTV at t0: Dmean=33.9 ± 20.8 Gy vs 52.2 ± 8.5 Gy (p=0.0009), D95%=27.5 ± 21 Gy vs 46.1 ± 4.8 Gy (p=0.004). Among the 12 patients with NF outside the elective nodal irradiation (ENI) volume, Dmean of NS outside the ENI was significantly lower (19.4 ± 21.4 Gy) than the Dmean of NS with failure within the ENI (45.1 ± 6.1 Gy, p=0.01). CONCLUSION: Loco-regional failure after exclusive chemoradiotherapy for esophageal cancer may be due to an inadequately low dose.

Assessment of aortic stiffness by local and regional methods.

The stiffness of large arteries has an important role in cardiovascular hemodynamics. Aortic stiffness (AoStiff) can be assessed non-invasively with regional and local methods. In this paper, we compared these two techniques for evaluating AoStiff. Our subjects comprised of 118 consecutive patients (85 men, mean age: 49 ± 14 years). We evaluated regional AoStiff with carotid-femoral pulse wave velocity (PWV) measured with a tonometric technique and by bioelectrical impedance (BI) wave velocity (IWV). The local AoStiff was calculated from BI signals recorded at the chest. We used glyceryl trinitrate (GTN) to test the effect of peripheral vasodilatation on both methods in a subgroup of 52 patients (37 men, mean age: 52 ± 11 years). We found a significant correlation between IWV and PWV measurements (r = 0.88, P < 0.0001) as well as between AoStiff and PWV measurements (r = 0.75, P < 0.0001). GTN administration decreased mean arterial blood pressure by 4% (95% confidence interval: 2-8%, P = 0.002) without significant changes in AoStiff and regional IWV. Local AoStiff is correlated with regional measurements and is not influenced by changes in arterial pressure because of systemic peripheral vasodilatation.