Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial.

BACKGROUND: Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC. METHODS: In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting. FINDINGS: Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1-52·3). Median event-free survival was not reached (95% CI 44·7 months-not reached) in the pembrolizumab group and 46·6 months (27·5-not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68-1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis). INTERPRETATION: Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Hedgehog Inhibitors Beyond Clinical Complete Response in Basal Cell Carcinoma: Should I Stop or Should I Go?

INTRODUCTION: In advanced basal cell carcinoma (BCC), the issue of whether Hedgehog inhibitors (HHIs) should be stopped or not after clinical complete response (cCR) achievement remains an unmet clinical need. MATERIALS AND METHODS: We conducted a retrospective, multicenter study across 7 Italian dermato-oncology units including patients with BCC who continued vismodegib after cCR between 2012 and 2019. We assessed the relationship between the duration of vismodegib intake (days to cCR [DTCR], days to stop after cCR [DTS], total treatment days [TTD]), and disease-free survival (DFS). Reasons to stop vismodegib were (R1) toxicity and (R2) disease recurrence. The relationship between DTCR, DTS, TTD, and DFS in the whole population and in R1 subgroup was assessed by Pearson's correlation coefficient (P < .05) and Bayesian statistics (BF10). RESULTS: Sixty-eight BCC patients with a median (m) age of 75.5 years (39-100) were included. Most patients were male (N = 43, 63%), without Gorlin syndrome (N = 56, 82%) and with head and neck area as primary site (N = 51, 75%). After cCR, out of 68 patients, 90% (N = 61/68) discontinued vismodegib: 82% (N = 50/61) due to toxicity (R1), and 18% (N = 11/61) due to recurrence (R2). Conversely, 10% (N = 7/68) continued vismodegib until last follow-up. In the whole population (N = 68), cCR was achieved with a mDTCR of 180.50 days. DFS showed a significant correlation with DTS (P < .01, BF10 = 39.2) and TTD (P < .01, BF10 = 35566), while it was not correlated to DTCR (BF10 < 0.1). The analysis of R1 subgroup (N = 50) confirmed these results. DFS correlated with DTS in all recurrent patients (N = 38, r = 0.44, P < .01) and in the recurrent patients who stopped vismodegib for toxicity (N = 26, r = 0.665, P < .01). DFS was longer when vismodegib was maintained for >2 months after cCR (mDFS > 2 months, N = 54 vs. ≤ 2 months, N = 14: 470 vs. 175 d, P < .01). CONCLUSIONS: Our retrospective results suggest that HHIs should be continued after cCR to improve DFS in BCC.

Developing a robust two-step machine learning multiclassification pipeline to predict primary site in head and neck carcinoma from lymph nodes.

This study aimed to develop a robust multiclassification pipeline to determine the primary tumor location in patients with head and neck carcinoma of unknown primary using radiomics and machine learning techniques. The dataset included 400 head and neck cancer patients with primary tumor in oropharynx, OPC (n = 162), nasopharynx, NPC (n = 137), oral cavity, OC (n = 63), larynx and hypopharynx, HL (n = 38). Two radiomic-based multiclassification pipelines (P1 and P2) were developed. P1 consisted in a direct identification of the primary sites, whereas P2 was based on a two-step approach: in the first step, the number of classes was reduced by merging the two minority classes which were reclassified in the second step. Diverse correlation thresholds (0.75, 0.80, 0.85), feature selection methods (sequential forwards/backwards selection, sequential floating forward selection, neighborhood component analysis and minimum redundancy maximum relevance), and classification models (neural network, decision tree, naïve Bayes, bagged trees and support vector machine) were assessed. P2 outperformed P1, with the best results obtained with the support vector machine classifier including radiomic and clinical features (accuracies of 75.3 % (HL), 75.4 % (OC), 71.3 % (OPC), 92.9 % (NPC)). These results indicate that the two-step multiclassification pipeline integrating radiomics and clinical information is a promising approach to predict the tumor site of unknown primary.

MRI radiomics in head and neck cancer from reproducibility to combined approaches.

The clinical applicability of radiomics in oncology depends on its transferability to real-world settings. However, the absence of standardized radiomics pipelines combined with methodological variability and insufficient reporting may hamper the reproducibility of radiomic analyses, impeding its translation to clinics. This study aimed to identify and replicate published, reproducible radiomic signatures based on magnetic resonance imaging (MRI), for prognosis of overall survival in head and neck squamous cell carcinoma (HNSCC) patients. Seven signatures were identified and reproduced on 58 HNSCC patients from the DB2Decide Project. The analysis focused on: assessing the signatures' reproducibility and replicating them by addressing the insufficient reporting; evaluating their relationship and performances; and proposing a cluster-based approach to combine radiomic signatures, enhancing the prognostic performance. The analysis revealed key insights: (1) despite the signatures were based on different features, high correlations among signatures and features suggested consistency in the description of lesion properties; (2) although the uncertainties in reproducing the signatures, they exhibited a moderate prognostic capability on an external dataset; (3) clustering approaches improved prognostic performance compared to individual signatures. Thus, transparent methodology not only facilitates replication on external datasets but also advances the field, refining prognostic models for potential personalized medicine applications.

Evasion of apoptosis and treatment resistance in squamous cell carcinoma of the head and neck.

Combinations of surgery, radiotherapy and chemotherapy can eradicate tumors in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN), but a significant proportion of tumors progress, recur, or do not respond to therapy due to treatment resistance. The prognosis for these patients is poor, thus new approaches are needed to improve outcomes. Key resistance mechanisms to chemoradiotherapy (CRT) in patients with LA SCCHN are alterations to the pathways that mediate apoptosis, a form of programmed cell death. Targeting dysregulation of apoptotic pathways represents a rational therapeutic strategy in many types of cancer, with a number of proteins, including the pro-survival B-cell lymphoma 2 family and inhibitors of apoptosis proteins (IAPs), having been identified as druggable targets. This review discusses the mechanisms by which apoptosis occurs under physiological conditions, and how this process is abnormally restrained in LA SCCHN tumor cells, with treatment strategies aimed at re-enabling apoptosis in LA SCCHN also considered. In particular, the development of, and future opportunities for, IAP inhibitors in LA SCCHN are discussed, in light of recent encouraging proof-of-concept clinical trial data.

Adenoid Cystic carcinoma of minor salivary glands (AdCCmSG): a multidisciplinary update.

INTRODUCTION: Adenoid cystic carcinoma of minor salivary glands (AdCCmSG) represents a 'rarity in the rarity,' posing a clinical challenge in lack of standardized, evidence-based recommendations. At present, AdCCmSG management is mostly translated from major salivary gland cancers (MSGCs). Ideally, AdCCmSG diagnostic-therapeutic workup should be discussed and carried out within a multidisciplinary, high-expertise setting, including pathologists, surgeons, radiation oncologists and medical oncologists. AREAS COVERED: The present review provides an overview of epidemiology and pathologic classification. Moreover, the most recent, clinically relevant updates in the treatment of AdCCmSG (Pubmed searches, specific guidelines) are critically discussed, aiming to a better understanding of this rare pathologic entity, potentially optimizing the care process, and offering a starting point for reflection on future therapeutic developments. EXPERT OPINION: The management of rare cancers is often hindered by limited data and clinical trials, lack of evidence-based guidelines, and hardly represented disease heterogeneity, which cannot be successfully tackled with a 'one-size-fits-all' approach. Our goal is to address these potential pitfalls, providing an easy-to-use, updated, multidisciplinary collection of expert opinions concerning AdCCmSG management as of today's clinical practice. We will also cover the most promising future perspectives, based on the potential therapeutic targets highlighted within AdCCmSG's molecular background.

Charged particle radiotherapy for thyroid cancer. A systematic review.

The role of external beam radiotherapy (EBRT) in thyroid cancer (TC) remains contentious due to limited data. Retrospective studies suggest adjuvant EBRT benefits high-risk differentiated thyroid cancer (DTC) and limited-stage anaplastic thyroid carcinoma (ATC), enhancing locoregional control and progression-free survival when combined with surgery and chemotherapy. Intensity-modulated radiotherapy (IMRT) and particle therapy (PT), including protons, carbon ions, and Boron Neutron Capture Therapy (BNCT), represent advances in TC treatment. Following PRISMA guidelines, we reviewed 471 studies from January 2002 to January 2024, selecting 14 articles (10 preclinical, 4 clinical). Preclinical research focused on BNCT in ATC mouse models, showing promising local control rates. Clinical studies explored proton, neutron, or photon radiotherapy, reporting favorable outcomes and manageable toxicity. While PT shows promise supported by biological rationale, further research is necessary to clarify its role and potential combination with systemic treatments in TC management.

Association of a gene-expression subtype to outcome and treatment response in patients with recurrent/metastatic head and neck squamous cell carcinoma treated with nivolumab.

BACKGROUND: Immune checkpoint inhibitors have been approved and currently used in the clinical management of recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. The reported benefit in clinical trials is variable and heterogeneous. Our study aims at exploring and comparing the predictive role of gene-expression signatures with classical biomarkers for immunotherapy-treated R/M HNSCC patients in a multicentric phase IIIb trial. METHODS: Clinical data were prospectively collected in Nivactor tiral (single-arm, open-label, multicenter, phase IIIb clinical trial in platinum-refractory HNSCC treated with nivolumab). Findings were validated in an external independent cohort of immune-treated HNSCC patients, divided in long-term and short-term survivors (overall survival >18 and <6 months since the start of immunotherapy, respectively). Pretreatment tumor tissue specimen from immunotherapy-treated R/M HNSCC patients was used for PD-L1 (Tumor Proportion Score; Combined Positive Score (CPS)) and Tumor Mutational Burden (Oncopanel TSO500) evaluation and gene expression profiling; classical biomarkers and immune signatures (retrieved from literature) were challenged in the NIVACTOR dataset. RESULTS: Cluster-6 (Cl6) stratification of NIVACTOR cases in high score (n=16, 20%) and low score (n=64, 80%) demonstrated a statistically significant and clinically meaningful improvement in overall survival in the high-score cases (p=0.00028; HR=4.34, 95% CI 1.84 to 10.22) and discriminative ability reached area under the curve (AUC)=0.785 (95% CI 0.603 to 0.967). The association of high-score Cl6 with better outcome was also confirmed in: (1) NIVACTOR progression-free survival (p=4.93E-05; HR=3.71, 95% CI 1.92 to 7.18) and objective-response-rate (AUC=0.785; 95% CI 0.603 to 0.967); (2) long survivors versus short survivors (p=0.00544). In multivariate Cox regression analysis, Cl6 was independent from Eastern Cooperative Oncology Group performance status, PDL1-CPS, and primary tumor site. CONCLUSIONS: These data highlight the presence of underlying biological differences able to predict survival and response following treatment with immunotherapy in platinum-refractory R/M HNSCC that could have translational implications improving treatment selection. TRIAL REGISTRATION NUMBER: EudraCT Number: 2017-000562-30.

Management of patients with rare adult solid cancers: objectives and evaluation of European reference networks (ERN) EURACAN.

About 500,000 patients with rare adult solid cancers (RASC) are diagnosed yearly in Europe. Delays and unequal quality of management impact negatively their survival. Since 2017, European reference networks (ERN) aim to improve the quality of care of patients with rare disease. The steering committee of EURACAN, including physicians, researchers and patients review here the previous actions, present objectives of the ERN EURACAN dedicated to RASC. EURACAN promoted management in reference centres, and equal implementation of excellence and innovation in Europe and developed 22 clinical practice guidelines (CPGs). Additionally, fourteen information brochures translated in 24 EU languages were developed in collaboration with patient advocacy groups (ePAGs) and seventeen training session were organized. Nevertheless, connections to national networks in the 26 participating countries (106 centres), simplification of cross-border healthcare, international multidisciplinary tumour boards, registries and monitoring of the quality of care are still required. In this Health Policy, evaluation criteria of the performances of the network and of health care providers are proposed.

Dietary intervention for tertiary prevention in head and neck squamous cell carcinoma survivors: clinical and translational results of a randomized phase II trial.

Background: There is a strong need for preventive approaches to reduce the incidence of recurrence, second cancers, and late toxicities in head and neck squamous cell carcinoma (HNSCC) survivors. We conducted a randomized controlled trial (RCT) to assess a dietary intervention as a non-expensive and non-toxic method of tertiary prevention in HNSCC survivors. Methods: Eligible participants were disease-free patients with HNSCC in follow-up after curative treatments. Subjects were randomized 1:1 to receive a highly monitored dietary intervention plus the Word Cancer Research Fund/American Institute for Cancer Research recommendations for cancer prevention (intervention arm) or standard-of-care recommendations (control arm). The planned sample size for the event-free survival evaluation (primary endpoint) was not reached, and the protocol was amended in order to investigate the clinical (nutritional and quality-of-life questionnaires) and translational study [plasma-circulating food-related microRNAs (miRNAs)] as main endpoints, the results of which are reported herein. Results: One hundred patients were screened, 94 were randomized, and 89 were eligible for intention-to-treat analysis. Median event-free survival was not reached in both arms. After 18 months, nutritional questionnaires showed a significant increase in Recommended Food Score (p = 0.04) in the intervention arm vs. control arm. The frequency of patients with and without a clinically meaningful deterioration or improvement of the C30 global health status in the two study arms was similar. Food-derived circulating miRNAs were identified in plasma samples at baseline, with a significant difference among countries. Conclusion: This RCT represented the first proof-of-principle study, indicating the feasibility of a clinical study based on nutritional and lifestyle interventions in HNSCC survivors. Subjects receiving specific counseling increased the consumption of the recommended foods, but no relevant changes in quality of life were recorded between the two study arms. Food-derived plasma miRNA might be considered promising circulating dietary biomarkers.