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.

Predictive value of health-related quality of life on radiotherapy-related toxicities in patients with head and neck cancer.

PURPOSE: Little is known about whether baseline health-related quality of life (HRQoL) scores also could predict occurrence radiotherapy-related toxicities, which we aim to assess in this study. METHODS: This study analyzed data from 200 patients enrolled in randomized study investigating the utility of HRQoL. HRQOL was assessed at baseline and during follow up using QLQ-C30 questionnaire and major toxicity was considered as adverse event ≥ 3 according to NCI-CTCAE classification. Cox regressions adjusting for clinical and sociodemographic data were used to assess prognostic significance of HRQOL scores. RESULTS: In multivariable analyses adjusted on clinical and sociodemographic data, every 10-point improvement in physical (HR = 0.74), role (HR = 0.87) and social (HR = 0.88) functioning was associated with 24%, 13% and 12% lower hazard of occurrence of major toxicity respectively while every 10 point-increase in dyspnea (HR = and loss appetite was associated with 15% and 16% increased hazard of major toxicity. CONCLUSION: Certain baseline HRQoL scores were found to be significantly associated with the occurrence of major toxicity.

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.

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.

Management of 80 sinonasal undifferentiated carcinomas. Retrospective multicentre study of the French Network of Rare Head and Neck Cancers (REFCOR).

OBJECTIVES: Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive disease requiring multimodal treatment, and multiple new entities once included in the spectrum of SNUC, such as SWI/SNF-deficient carcinomas, are emerging. We aimed to provide new data regarding the role of chemotherapy and surgery and the prognostic factors of disease-free survival. METHODS: This study was based on data from the REFCOR database and included patients with SNUC treated with curative intent from 2007 to 2021 across 22 centres in France. RESULTS: A total of 80 patients were included in the analysis. Among the entire cohort, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 58% and 63%, respectively. Of 100% of the patients treated with irradiation, 29% underwent surgery, 56% neoadjuvant chemotherapy (82% had either a partial or a complete response) and 76% chemoradiotherapy. No treatment modality was associated with a better OS or DFS, including surgery (p = 0.34). There was a trend for a better DFS for the patients treated with chemotherapy (neoadjuvant or concomitant, p = 0.062). Overall survival at 3 years was 58% for SWI/SNF deficient group and 86% for non deficient group (p = 0.14). The locoregional relapse rate without distant metastases was 21% in the exclusive radiotherapy group and 26% in the surgery group. Grade 3 or higher toxicities concerned 9%, 32% and 29% of patients for surgery, radiotherapy and chemotherapy respectively. CONCLUSION: In the management of localised SNUC among all patients treated with irradiation, surgery yielded no benefit, whereas the addition of chemotherapy tended to improve disease-free survival.

Randomized Trial Assessing the Impact of Routine Assessment of Health-Related Quality of Life in Patients with Head and Neck Cancer.

The impact of routine assessment of health-related quality of life (HRQoL) on satisfaction with care and the HRQoL of patients with head and neck cancer (HNC) treated with radiotherapy was assessed. Patients with HNC were randomly assigned to two arms, with stratification on sex, cancer localization, and stage of the disease. In the intervention arm, the patients completed the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires first before randomization, then before each medical appointment during radiotherapy (7 weeks), and then every 3 months until 1 year and at 2 years thereafter. In the control arm, the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires were completed before randomization and at 1 year and 2 years thereafter. The primary endpoint was mean change in HRQoL at score at 2 years from baseline assessed by EQ VAS from the EuroQol questionnaire. The secondary endpoint was mean change in satisfaction with care at 2 years from baseline assessed by QLQ-SAT32. Two hundred patients with head and neck cancers were involved in this study (mean age, 58.83 years (range, 36.56-87.89)), of whom 100 were assigned to the intervention arm and 100 to the control arm. Patients in the intervention arm were reported to have a statistically significant increase in EQ VAS at 2 years (p < 0.0001) and exceeded the minimal clinically important difference (mean change at 2 years from baseline = 10.46). In the two arms, mean differences between arms were not statistically significant, but minimal clinically important differences in favor of the intervention arm were found for EQ VAS (mean change difference (MD) = 5.84), satisfaction with care, in particular waiting times (MD = 10.85) and satisfaction with accessibility (MD = 6.52). Routine assessment of HRQoL improves HRQoL and satisfaction with care for patients with HNC treated with radiotherapy.

Recommendations for postoperative radiotherapy in head & neck squamous cell carcinoma in the presence of flaps: A GORTEC internationally-reviewed HNCIG-endorsed consensus.

INTRODUCTION: Head and neck reconstructive surgery using a flap is increasingly common. Best practices and outcomes for postoperative radiotherapy (poRT) with flaps have not been specified. We aimed to provide consensus recommendations to assist clinical decision-making highlighting areas of uncertainty in the presence of flaps. MATERIAL AND METHODS: Radiation, medical, and surgical oncologists were assembled from GORTEC and internationally with the Head and Neck Cancer International Group (HNCIG). The consensus-building approach covered 59 topics across four domains: (1) identification of postoperative tissue changes on imaging for flap delineation, (2) understanding of tumor relapse risks and target volume definitions, (3) functional radiation-induced deterioration, (4) feasibility of flap avoidance. RESULTS: Across the 4 domains, international consensus (median score ≥ 7/9) was achieved only for functional deterioration (73.3%); other consensus rates were 55.6% for poRT avoidance of flap structures, 41.2% for flap definition and 11.1% for tumor spread patterns. Radiation-induced flap fibrosis or atrophy and their functional impact was well recognized while flap necrosis was not, suggesting dose-volume adaptation for the former. Flap avoidance was recommended to minimize bone flap osteoradionecrosis but not soft-tissue toxicity. The need for identification (CT planning, fiducials, accurate operative report) and targeting of the junction area at risk between native tissues and flap was well recognized. Experts variably considered flaps as prone to tumor dissemination or not. Discrepancies in rating of 11 items among international reviewing participants are shown. CONCLUSION: International GORTEC and HNCIG-endorsed recommendations were generated for the management of flaps in head and neck radiotherapy. Considerable knowledge gaps hinder further consensus, in particular with respect to tumor spread patterns.

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.

Patterns of Failure in Patients With Head and Neck Squamous Cell Carcinomas of Unknown Primary Treated With Chemoradiotherapy.

BACKGROUND: To evaluate the patterns of failure in patients treated for head and neck carcinoma of unknown primary and to discuss treatment practices concerning radiotherapy target volumes definition and dose prescription. METHODS: Eleven patients presenting a locoregional recurrence after head and neck carcinoma of unknown primary treatment with curative-intent radiochemotherapy performed between 2007 and 2017 in the departments of radiation oncology of 2 French cancer institutes. Images of the computed tomography scan or the magnetic resonance imaging performed at the time of the recurrence were fused with those of the simulation computed tomography scan to delimit a volume corresponding to the recurrence and to define the area of relapse compared to the volumes treated. RESULTS: Irradiation was unilateral in 6 cases and bilateral in 5 cases. The median time to onset of recurrence was 7.24 months (extreme 3-67.7 months). Six patients had only a neck node recurrence, 3 had a neck node and subsequent primary recurrence, and 1 had only a median subsequent primary recurrence. Only 1 patient had synchronous distance progression to local recurrence. All neck node recurrences were solitary and ipsilateral. The subsequent primary recurrences were in the oropharynx in 3 cases and in the contralateral oral cavity in one case. All neck node recurrences were into the irradiated volume. The subsequent primary recurrences were either within or in border of the irradiated volumes. The median of the mean dose, received by neck node recurrences, was 69.9 Gy and that of the mean dose, minimum dose, maximum dose, and dose received by 95% of the volume of recurrence was 66.7 Gy. For the primary relapses, the median of the mean dose was 52.1 Gy and that of the mean dose, minimum dose, maximum dose, and dose received by 95% of the volume of recurrence was 39.9 Gy. CONCLUSIONS: All local nodal recurrences occurred at sites that received high radiotherapy doses and doses received by sites of eventual failure did not vary significantly from sites that remain in control.

[Diagnostic and treatment pitfalls and guidelines for variants of squamous cell carcinomas of the head and neck: on behalf of the REFCOR]. / Variants des carcinomes épidermoïdes dans les voies aérodigestives supérieures (VADS), implications pour le diagnostic et la prise en charge, selon les référentiels du REFCOR.

Among the 20,000 new cases of head and neck neoplasms in France each year, squamous cell carcinomas (HNSCC) represent about 90 % of the cases. Among these, variants of conventional squamous cell carcinomas represent between 5% and 10% of cases. Patient history and risk factors are often similar from those of conventional HSNCC. Variants may, however, be misdiagnosed, which can lead to therapeutic mismanagement due to confusion with sarcomas, glandular tumors or even benign tumors. Diagnostic workup needs to be more cautionary or to include additional exams not to omit their most aggressive component in the case of composite tumors or to under stage the tumor. Immunohistochemistry and specific molecular analyses may be required for proper diagnosis. Central pathological review may also be essential for some of these variants. In addition, some variants are radioresistant and, conversely, others are radiosensitive. An update of the REFCOR 2008 standards was carried out in the light of the international literature and the 2017 WHO/IARC classification for the seven main variants of HNSCC, verrucous, acantholytic (to be named adenoid carcinomas), basaloid, papillary, spindle cell (incorrectly named sarcomatoid), adenosquamous and lymphoepithelial carcinomas.

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.

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.