Head and neck cancers (HNC) represent the seventh most frequent cancer worldwide, with squamous cell carcinomas as the most frequent histologic subtype. Standard treatment for early stage diseases is represented by single modality surgery or radiotherapy, whereas in the locally advanced and recurrent or metastatic settings a more aggressive multi-modal approach is needed with locoregional intervention and/or systemic therapies. Epidermal Growth Factor Receptor (EGFR) plays an important role in HNC biology and has been studied extensively in preclinical and clinical settings. In this scenario, anti-EGFR targeted agent cetuximab, introduced in clinical practice a decade ago, represents the only approved targeted therapy to date, while the development of immune-checkpoint inhibitors has recently changed the available treatment options. In this review, we focus on the current role of anti-EGFR therapies in HNCs, underlying available clinical data and mechanisms of resistance, and highlight future perspectives regarding their role in the era of immunotherapy.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with 20% of patients presenting with metastatic disease at diagnosis. TGF-β signaling plays a crucial role in various cellular processes, including growth, differentiation, apoptosis, epithelial-mesenchymal transition (EMT), regulation of the extracellular matrix, angiogenesis, and immune responses. TGF-β signals through SMAD proteins, which are intracellular molecules that transmit TGF-β signals from the cell membrane to the nucleus. Alterations in the TGF-β pathway and mutations in SMAD proteins are common in metastatic CRC (mCRC), making them critical factors in CRC tumorigenesis. This review first analyzes normal TGF-β signaling and then investigates its role in CRC pathogenesis, highlighting the mechanisms through which TGF-β influences metastasis development. TGF-β promotes neoangiogenesis via VEGF overexpression, pericyte differentiation, and other mechanisms. Additionally, TGF-β affects various elements of the tumor microenvironment, including T cells, fibroblasts, and macrophages, promoting immunosuppression and metastasis. Given its strategic role in multiple processes, we explored different strategies to target TGF-β in mCRC patients, aiming to identify new therapeutic options.

The Hepatocyte growth factor (HGF)—mesenchymal-epithelial transition (MET) pathway is deregulated in several cancers and is associated with aggressive phenotype and worse prognosis. MET, a tyrosine kinase receptor activated by HGF, plays a physiological role in embryogenesis, promoting cell growth, survival and motility. HGF–MET aberrant activation in tumorigenesis acts through various mechanisms: paracrine/autocrine HGF production, MET overexpression, MET germ-line and sporadic mutations and cross-talk with other growth factor receptors. In addition, MET activation could represent a mechanism of escape from other targeted therapies, through receptor amplification or over-stimulation by the ligand, as demonstrated in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) models with acquired resistance to epidermal growth factor receptor (EGFR) inhibitors and also in models of melanoma resistant to the BRAF inhibitor vemurafenib. As a consequence, a lot of molecules targeting MET signaling are under clinical investigation as single agent or in combination with other targeted drugs. Patient selection, based on MET expression on tumor samples (eventually, by re-biopsy of new metastatic sites), and pharmacokinetic/pharmacodynamic markers are needed. Authors review the latest data on the role of MET and the molecular mechanism underlying primary or acquired resistance to biological agents, focusing on NSCLC, CRC and melanoma.

Head and neck squamous cell carcinomas (HNSCC) constitute the sixth most common malignancy worldwide, with approximately 25–40% of the diagnosed patients older than 70 years. HNSCC patients are often frail and frequently have multiple comorbidities due to their unhealthy lifestyle, and evidence suggests that older patients may receive less aggressive and suboptimal treatment than younger patients with the same disease status. The aim of this review is to depict and summarize the evidence regarding the different strategies that can be used in the clinical management of elderly HNSCC patients. Key references were derived from a PubMed query. Hand searching and clinicaltrials.gov were also used. This paper contains a narrative report and a critical discussion of clinical approaches in the context of elderly HNSCC.

Background: health-related quality of life (HRQOL) represents a secondary endpoint of medical interventions in oncological patients. Our aim was to highlight potential sources of bias that could be encountered when evaluating HRQOL in oral cancer patients. Methods: this review followed PRISMA-ScR recommendations. Participants: patients treated for oral cancer. Concept: HRQOL assessed by EORTC QLQ-C30 and QLQ-H&N35/QLQ-H&N43. A critical appraisal of included studies was performed to evaluate the accuracy of data stratification with respect to HRQOL determinants. Results: overall, 30 studies met the inclusion criteria, totaling 1833 patients. In total, 8 sociodemographic (SDG) and 15 disease/treatment-specific (DT) HRQOL determinants (independent variables) were identified. The mean number of the independent variables was 6.1 (SD, 4.3)—5.0 (SD, 4.0) DT-related and 1.1 (SD, 1.8) SDG-related variables per article. None of the included papers considered all the identified determinants simultaneously. Conclusions: a substantial lack of evidence regarding HRQOL determinants was demonstrated. This strongly weakens the reliability of the reported findings due to the challenging presence of baseline confounding, selection, and omitted variable biases. The proposed approach recommends the use of further evaluation tools that gather more variables in a single score together with a selection of more homogeneous, reproducible, and comparable cohorts based on the identified baseline confounding.

Checkpoint inhibitors (ICIs) have demonstrated substantial efficacy in the treatment of numerous solid tumors, including head and neck cancer. Their inclusion in the therapeutic paradigm in metastatic lines of treatment has certainly improved the outcomes of these patients. Starting from this assumption, numerous studies have been conducted on ICIs in other earlier disease settings, including studies conducted in patients in neoadjuvant settings. However, how many and which studies are truly significant? Can they lay concrete foundations for further future studies and therefore allow us to continue to have this interesting future perspective? Through a review of the existing literature, coupled with insights gleaned from clinical practice and from the main recently published studies, we aim to examine the therapeutic potential of ICIs in patients affected by head and neck cancer in a neoadjuvant treatment setting and encourage researchers to set up successful future clinical trials.