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.

Definitive radio(chemo)therapy versus upfront surgery in the treatment of HPV-related localized or locally advanced oropharyngeal squamous cell carcinoma.

BACKGROUND: The treatment of stage I-III HPV+ oropharyngeal squamous cell carcinoma (HPV-OPSCC) is based on either surgery ± adjuvant therapy or exclusive radio±chemotherapy. We sought to compare these two therapeutic strategies in terms of efficacy, tolerance and quality of life (QoL). METHODS: Patients treated for stage I-III HPV-OPSCC from 2010 to 2021 in 3 academic centers were included and sorted according to the treatment strategy: surgery or exclusive radio±chemotherapy. Efficacy and tolerance were retrospectively assessed, and a transversal exploratory QoL assessment was performed using QoL instruments. RESULTS: A total of 83 patients were included, with 21 undergoing non-minimally invasive surgery and 62 receiving definitive radio-±chemotherapy. 2-year progression-free survival (PFS) and overall survival (OS) were respectively 80% and 86% in the surgical group and 92% and 95% in the non-surgical group, with no significant difference. At the end of treatment, 64.5% of patients presented with a grade III toxicity, without significant difference between the two groups. No patient had late grade III toxicity at 24 months. Forty-five patients (11 in the surgical group, 34 in the non-surgical group) participated in an exploratory quality-of-life analysis. Patients reported significantly more fatigue and loss of appetite after surgery, whereas patients in the radio±chemotherapy group described significantly more salivary and oral problems and difficulty swallowing, but the median time between treatment completion and the response to the questionnaires. CONCLUSION: There was no significant difference in efficacy, physician-reported toxicity and overall patient-reported quality of life was found between non-minimally invasive surgery and radio±chemotherapy in the treatment of stage I-III HPV-OPSCC.

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.

Phase II study of concomitant radiotherapy with atezolizumab in oligometastatic soft tissue sarcomas: STEREOSARC trial protocol.

INTRODUCTION: Up to 50% of soft tissue sarcoma (STS) patients develop metastases in the course of their disease. Cytotoxic therapy is a standard treatment in this setting but yields average tumour response rates of 25% at first line and ≤10% at later lines. In oligometastatic stage, stereotactic body radiation therapy (SBRT) allows reaching high control rates at treated sites (≥80%) and is potentially equally effective to surgery in term of overall survival. In order to shift the balance towards antitumour immunity by multisite irradiation, radiation could be combined with inhibitors of the immunosuppressive pathways. METHODS AND ANALYSIS: STEREOSARC is a prospective, multicentric, randomised phase II, designed to evaluate the efficacy of SBRT associated with immunotherapy versus SBRT only. Randomisation is performed with a 2:1 ratio within two arms. The primary objective is to evaluate the efficacy, in term of progression-free survival (PFS) rate at 6 months, of immunomodulated stereotactic multisite irradiation in oligometastatic sarcoma patients. The secondary objectives include PFS by immune response criteria, overall survival, quality-of-life evaluation and developing mathematical models of tumour growth and dissemination predictive of oligometastatic versus polymetastatic evolution. Patients will be randomised in two groups: SBRT with atezolizumab and SBRT alone. The total number of included patients should be 103. TRIAL REGISTRATION: The trial is registered on ClinicalTrials.gov (ID: NCT03548428). ETHICS AND DISSEMINATION: This study has been approved by Comité de Protection des Personnes du sud-ouest et outre-mer 4 on 18 October 2019 (Reference CPP2019-09-076-PP) and from National Agency for Medical and Health products Safety (Reference: MEDAECNAT-2019-08-00004_2017-004239-35) on 18 September 2019.The results will be disseminated to patients upon individual request or through media release from scientific meetings. The results will be communicated through scientific meetings and publications.

Limbs and trunk soft tissue sarcoma systematic local and remote monitoring by MRI and thoraco-abdomino-pelvic scanner: A single-centre retrospective study.

INTRODUCTION: Soft tissue sarcomas (STS) are rare malignant tumors that require management by an expert center. Monitoring modalities are not consensual. The objective of our study is to report systematic radiological monitoring data obtained by local MRI and by thoracic-abdominal-pelvic computed tomography (TAP CT). MATERIAL AND METHODS: 113 consecutive patients managed at "Centre Georges François Leclerc, Dijon", between 2008 and 2016, for an initially localized STS were included. Patient follow-up consisted of a local MRI and a TAP CT. Follow-up exams schedule was initially every 4 months during 2 years, followed by every 6 months during 3 years and finally every year during 5 years. RESULTS: Median follow-up time was 37.2 months [min = 2.4 - max = 111.6]. After 5 years of surveillance, local recurrence (LR) rate was 8.8% and diagnosed by imaging in 60% of cases. No deep LR was clinically found. Median LR diagnosis time was 23.9 months [min = 2.0 - max = 52.4]. 50% of patients locally treated for their LR were alive without recurrence. Metastatic recurrence (MR) rate was 31%. 42.8% had extra-pulmonary involvement and 17.1% had exclusive extrathoracic metastases. The median time to diagnosis of MR was 17.4 months [min = 2.7- max = 77.2]. High-grade tumors relapsed more (20.4%) and earlier (all before the 5th year) than low grade. CONCLUSION: Local MRI seems particularly suitable for monitoring deep tumors. In addition, the systematic monitoring by TAP CT highlighted a limited number of cases of exclusive extrathoracic metastases. The schedule of local and remote monitoring should primarily be adjusted to tumor grade.

Hypofractionated Stereotactic Radiotherapy as a Salvage Therapy for Recurrent High-Grade Gliomas: Single-Center Experience.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the survival outcomes and safety of hypofractioned stereotactic radiotherapy as a salvage treatment for recurrent high-grade glioma. PATIENTS AND METHODS: Between March 2012 and March 2017, 32 consecutive patients (12 women, 20 men) treated in a single center were retrospectively included in this study. Grade III gliomas were diagnosed in 14 patients and grade IV in 18 patients. Thirty-four lesions were treated with hypofractionated stereotactic radiotherapy on a linear accelerator. Hypofractionated stereotactic radiotherapy delivered a median dose of 30 Gy (27-30) in 6 fractions (3-6) of 5 Gy (5-9). The treatment plans were normalized to 100% at the isocenter and prescribed to the 80% isodose line. Clinical outcomes and prognostic factors were analyzed. RESULTS: Median follow-up was 20.9 months. Median overall survival following hypofractionated stereotactic radiotherapy was 15.6 months (median overall survival for patients with glioblastoma and grade III glioma was 8.2 and 19.5 months, respectively; P = .0496) and progression-free survival was 3.7 months (median progression-free survival for patients with glioblastoma and grade III glioma was 3.6 and 4.5 months, respectively; P = .2424). In multivariate analysis, tumor grade III ( P = .0027), an Eastern Cooperative Oncology Group status <2 at the time of reirradiation ( P = .0023), and a mean dose >35 Gy ( P = .0055) significantly improved overall survival. A maximum reirradiation dose above 38 Gy ( P = .0179) was significantly associated with longer progression-free survival. CONCLUSION: Hypofractionated stereotactic radiotherapy is well tolerated and offers an effective salvage option for the treatment of recurrent high-grade gliomas with encouraging overall survival. Our results suggest that the dose distribution had an impact on survival.