Why Oncologists Should Feel Directly Involved in Persuading Patients with Head and Neck Cancer to Quit Smoking.

INTRODUCTION: Among the risk factors for squamous cell carcinoma of the head and neck, smoking is still the most important today. Several studies agree on the effect of smoking on tumor microenvironment, while the definition of former smokers and the time of smoking cessation on biologic effect differs among papers. METHODS: We conducted a narrative review on smoking effects in HNSCC. RESULTS: There is evidence that smoker patients have a poorer prognosis than never smokers and former smokers. Translational studies show a relationship between smoking status and gene expression and support the importance of smoking cessation, for instance, demonstrating an inverse relationship between tumor-infiltrating lymphocytes and smoking. CONCLUSION: Convincing data suggest that quitting smoking at any time may improve patient outcomes. We advocate smoking cessation also after cancer diagnosis.

A Multidisciplinary Approach to Patients with Psoriasis and a History of Malignancies or On-Treatment for Solid Tumors: A Narrative Literature Review.

Psoriasis is a chronic immune-mediated disease that is linked to an increased risk of cancer. Although numerous studies have explored whether neoplasms are concurrent conditions or are induced by psoriasis, a definitive definition remains elusive. In this study, we conducted a comprehensive narrative literature review to offer practical guidance to oncologists and dermatologists regarding the initiation and discontinuation of biologics for psoriasis. The findings indicate that a customized approach is recommended for each patient, and that a history of malignancies does not constitute an absolute contraindication for biologics. Growing evidence supports the treatment of selected patients, emphasizing a nuanced assessment of benefits and risks. There is a lack of data specifying a safe timeframe to initiate biologics following a neoplasm diagnosis due to influences from cancer-related and patient-specific characteristics impacting prognosis. Some patients may continue anti-psoriasis therapy during cancer treatments. Enhanced comprehension of the biological mechanisms in cancer progression and the immune microenvironment of psoriasis holds promise for refining therapeutic strategies. In conclusion, a personalized treatment approach necessitates collaboration between oncologists and dermatologists, considering factors such as cancer prognosis, psoriasis clinical manifestations, patient characteristics, and preferences when making treatment decisions.

Immune escape mechanisms in head and neck squamous cell carcinoma and implication for new immunotherapy approach.

PURPOSE OF REVIEW: The aim of this review is to describe the major steps leading to the immunosuppressive tumor microenvironment and to summarize some of the new immunotherapies that interfere with these mechanisms. RECENT FINDINGS: Immunotherapy has improved the outcome of relapsed/metastatic head and neck squamous cell carcinoma (HNSCC). However, most patients still do not respond to treatment and median overall survival remains short with a modest rate of long-term survivors. There is a growing awareness that tumor immune-escape is a complex process that involves many redundant mechanisms other than immune check-points. They interfere with the innate immune response, activation of adaptive immune response, homing of effector T cells, their clonal expansion, viability, and efficiency. This abundance of immunosuppressive mechanisms explains the limited results achieved by immune checkpoint inhibitors. Combined treatments targeting different mechanisms of escape are in development to further improve the outcome of patients with HNSCC. SUMMARY: Many mechanisms favor tumor immune-escape. Each tumor exploits preferably some of them and the challenge is to understand which are the best targets in each tumor. This knowledge is an important tool to design future combination strategies based on strong biological rationales, which could offer better results than simple empirical combinations.

Phase III Randomized Study of Induction Chemotherapy Followed by Definitive Radiotherapy + Cetuximab Versus Chemoradiotherapy in Squamous Cell Carcinoma of Head and Neck: The INTERCEPTOR-GONO Study (NCT00999700).

OBJECTIVES: Induction chemotherapy followed by cetuximab and RT (IBRT) (Arm A) was compared to cisplatin/RT (CRT) (Arm B) in a randomized phase III study. PATIENTS AND METHODS: Naïve patients with stage III-IVa, histologically proven locally advanced head and neck cancer (LASCCHN) were eligible. Arm A (IBRT): 3 TPF induction followed by cetuximab-RT (equivalent daily dose 2 Gy up to 70 Gy); Arm B: 3 cisplatin concurrent with the same RT scheduling. Due to slow accrual and incomplete data collection a futility analysis was performed. RESULTS: 236/282 patients were evaluable. Therefore, no formal analyses can be made between the two arms. OS was 45.2/53.6 months in Arm A/B. Complete responses were achieved in 64% of patients in both arms. Neutropenia and skin toxicity were significantly worse in Arm A and body weight loss was significantly worse in Arm B. Compliance with the planned drug administration was higher in Arm B (p = 0.0008). CONCLUSION: The study suggests that IBRT and CRT have similar efficacy, activity and toxicity.

Lenvatinib Long-Term Responses in Refractory Thyroid Cancer: Our Mono-Institutional Real-Life Experience with the Multidisciplinary Approach and Review of Literature.

Lenvatinib (LEN) is a multikinase inhibitor with antiangiogenic properties recently approved in radioactive iodine-refractory differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma in combination with everolimus. LEN-treated patients frequently have adverse events (AEs) that generally require such dose modifications, including drug discontinuation. Hypertension, diarrhea, weight loss, proteinuria, fatigue, and palmar-plantar erythrodysesthesia are reported among the most frequent AEs, often leading to discontinuations or dose modifications. This paper reports a case series focusing on the role of the immediate multidisciplinary approach to manage AEs.

Predictors of Patient-Reported Dysphagia Following IMRT Plus Chemotherapy in Oropharyngeal Cancer.

The aim of this cross-sectional study is to evaluate the factors associated with patient-reported dysphagia in patients affected by locally advanced oropharyngeal cancer (OPC) treated with definitive intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy (CHT), with or without induction CHT. We evaluated 148 OPC patients treated with IMRT and concurrent CHT, without evidence of disease and who had completed their treatment since at least 6 months. At their planned follow-up visit, patients underwent clinical evaluation and completed the M.D. Anderson dysphagia inventory (MDADI) questionnaire. The association between questionnaire composite score (MDADI-CS) and different patients' and tumor's characteristics and treatments (covariates) was investigated by univariable and multivariable analyses, the latter including only covariates significant at univariable analysis. With a median time from treatment end of 30 months [range 6-74 months, interquartile range (IQR) 16-50 months], the median (IQR) MDADI-CS was 72 (63-84). The majority of patients (82.4%) had a MDADI-CS ≥ 60. At multivariable analysis, female gender, human papilloma virus (HPV)-negative status, and moderate and severe clinician-rated xerostomia were significantly associated with lower MDADI-CS. Patient-perceived dysphagia was satisfactory or acceptable in the majority of patients. HPV status and xerostomia were confirmed as important predictive factors for swallowing dysfunction after radiochemotherapy. Data regarding female gender are new and deserve further investigation.

Pros and Cons of the New Edition of TNM Classification of Head and Neck Squamous Cell Carcinoma.

The TNM classification is a worldwide standard staging system used to define the extent of cancer and is a major prognostic factor in predicting the outcome of patients. The TNM Classification of Malignant Tumours, 8th edition, has been used since January 1, 2018. In the area of head and neck cancer major modifications were produced: important updated T and N modification for oral cavity and nasopharyngeal cancer, the introduction of clinical and pathological stages for neck disease, and a new HPV-16-positive HNSCC classification. While until a few years ago the TNM staging system classified prognostic risk groups based on tumour size, the 8th edition responds to the need to categorize the prognosis of patients with similarly sized tumours but with very different clinical and biological behaviour. This review details TNM changes and the clinical need for these modifications, valuating possible limits in daily applicability.

Elevated basal antibody-dependent cell-mediated cytotoxicity (ADCC) and high epidermal growth factor receptor (EGFR) expression predict favourable outcome in patients with locally advanced head and neck cancer treated with cetuximab and radiotherapy.

BACKGROUND: Antibody-dependent cell-mediated cytotoxicity (ADCC) may contribute to the antitumor activity of cetuximab. However, the extent of this contribution is unclear. In this study, we investigated the impact of baseline ADCC on the outcome of patients with locally advanced squamous cell carcinoma treated with cetuximab and radiotherapy. METHODS: We determined baseline ADCC in 28 patients treated with cetuximab and radiotherapy and in 15 patients treated with chemoradiation. We linked the values observed with complete response and with overall survival. We also considered the role of epidermal growth factor receptor (EGFR) expression and studied the combined effect of EGFR and ADCC. RESULTS: We observed a wide range of baseline values of ADCC. Complete response did not correlate with either ADCC or EGFR expression. However, when ADCC and EGFR were considered together using a mixed score, they significantly correlated with achieving a complete response (p = 0.04). High baseline ADCC significantly correlated with outcome compared to low (p = 0.03), but not in patients treated without cetuximab. Patients showing high baseline levels of both ADCC and EGFR3+ achieved the best outcome compared to the others (p = 0.02). CONCLUSIONS: In this study, patients treated with cetuximab and radiotherapy, showing high baseline of both ADCC and EGFR3+, have significant higher probability of achieving a complete response and a long overall survival compared to the others.

State-of-the-art and emerging treatment options in the management of head and neck cancer: news from 2013.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer death worldwide. Its treatment is complex and evolving. In general, early-stage disease may be managed with single-modality treatment while an advanced stage (about 60% of clinical presentation) needs a multidisciplinary approach. In this setting concurrent chemoradiation has been associated with improvement in locoregional control and organ preservation, but at the cost of significant acute and chronic toxicity. Molecular target therapies specially directed to epidermal growth factor receptor (EGFR) might improve the outcomes and reduce toxicities. In recurrent-metastatic (R/M) HNSCC, cetuximab, a monoclonal antibody against EGFR, plus platinum-based chemotherapy (CT) allow an overall survival (OS) of about 10 months. However, the prognosis for R/M-HNSCC remains dismal and additional efforts are needed. At the 2013 American Society of Clinical Oncology (ASCO) Meeting, data on induction CT, anti-EGFR inhibitors, innovative molecular targets and predictor factors were reported. Further results on target therapies were presented at the European Cancer Congress (ECC) 2013, where a large study also showed that hyperfractionated radiotherapy (RT) improve OS rates compared with standard RT. The aim of this review is to discuss current standards and emerging therapies by considering recent new updates. © 2014 S. Karger AG, Basel.

Gorlin Syndrome-Associated Basal Cell Carcinomas Treated with Vismodegib or Sonidegib: A Retrospective Study.

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome (GS), is a genetic disorder characterized by the development of multiple cutaneous BCCs due to mutations in the hedgehog signaling pathway. The use of hedgehog pathway inhibitors-vismodegib and sonidegib-has emerged as a promising therapeutic strategy for managing BCCs in individuals with GS. In a retrospective study conducted between March 2012 and January 2024, a cohort of 16 Gorlin syndrome patients who received treatment with either sonidegib or vismodegib were analyzed. The primary objectives of the study were to evaluate the efficacy, safety profile, and duration of response to oral hedgehog inhibitors in this patient population. The study assessed various parameters, including the number of new BCCs that developed before and after treatment initiation, the duration and sustainability of treatment responses, as well as the incidence of adverse effects associated with hedgehog inhibitor therapy. The findings of the study revealed that sustained treatment with hedgehog inhibitors could effectively suppress the progression of both new and existing BCCs. Furthermore, the results indicated that sonidegib exhibited superior efficacy and safety compared to vismodegib in the treatment of BCCs in individuals with GS. Notably, adjustments to the administration schedule of sonidegib were found to improve tolerability without compromising therapeutic efficacy, potentially leading to prolonged durations of treatment response and disease control.

Survival of Patients with Sinonasal Cancers in a Population-Based Registry, Lombardy, Italy, 2008-2023.

Sinonasal cancers (SNCs) are rare malignancies associated with occupational exposures. The aim of this study was to analyse the survival of SNC patients using data from the population-based SNC registry of the Lombardy region (10 million people), Italy. We included epithelial SNC cases registered in 2008-2020 and followed-up for vital status until 31 July 2023. Multivariate flexible parametric models with time-dependent covariates were fitted to calculate excess hazard ratios (EHRs) and 95% confidence intervals (CIs) of death. Based on 827 cases (553 males, 274 females) and 514 deaths (345 males, 169 females), the 5-year observed survival was 49% and the net survival was 57%. Age had a substantial impact on survival, particularly within the first year (EHR, 1.35; 95% CI, 1.12-1.51 per 10 years). Compared with the nasal cavity, the EHR for paranasal sinuses was 4.70 (95% CI, 2.96-7.47) soon after diagnosis. Compared with squamous cell carcinomas, the EHR was 0.69 (95% CI, 0.52-0.91) for adenocarcinomas, 1.68 (95% CI, 1.20-2.35) for undifferentiated and unspecified carcinomas, and 1.78 (95% CI, 1.07-2.95) for neuroendocrine carcinomas. Age and cancer site showed time-dependent effects on prognosis, especially within the first month after diagnosis. Prognosis was also markedly affected by cancer morphology. No associations were found for gender and period of diagnosis.

Malignant Pleural Mesothelioma: Staging and Radiological Response Criteria in Patients Treated with Immune Checkpoint Inhibitors.

Malignant pleural mesothelioma (MPM) is a rare and challenging cancer associated with asbestos fiber exposure, which offers limited treatment options. Historically, platinum-based chemotherapy has been the primary approach, but recent developments have introduced immunotherapy as a promising alternative for the treatment of this disease. Nevertheless, the unique growth patterns and occasionally ambiguous progressive characteristics of MPM make the interpretation of radiological assessments complex. Immunotherapy further complicates matters by introducing unconventional treatment response patterns such as hyperprogression and pseudoprogression. Consequently, there is a growing imperative to integrate the standard RECIST criteria with the mesothelioma-specific mRECIST criteria (version 1.1), as outlined in iRECIST. This comprehensive review is driven by the intent to provide a valuable resource for radiologists and clinicians engaged in the diagnosis, treatment, and monitoring of MPM in the era of immunotherapy. Specifically, the current imaging methods employed for staging and follow-up will be exposed and discussed, with a focus on the technical specificities and the mRECIST 1.1 methodology. Furthermore, we will provide a discussion about major clinical trials related to the use of immunotherapy in MPM patients. Finally, the latest advancements in radiomics, the applications of artificial intelligence in MPM, and their potential impact on clinical practice for prognosis and therapy, are discussed.

Hormone Receptor-Positive/HER2-Positive Breast Cancer: Hormone Therapy and Anti-HER2 Treatment: An Update on Treatment Strategies.

Hormone receptor (HR)-positive/HER2-positive breast cancer represents a distinct subtype expressing estrogen and progesterone receptors with an overexpression of HER2. Approximately 14% of female breast cancer cases are HER2-positive, with the majority being HR-positive. These tumors show a cross-talk between the hormonal and HER2 pathways; the interaction has implications for the treatment options for the disease. In this review, we analyze the biology of HR-positive/HER2-positive breast cancer and summarize the evidence concerning the standard of care options both in neoadjuvant/adjuvant settings and in advanced disease. Additionally, we focus on new trials and drugs for HR-positive/HER2-positive breast cancer and the new entity: HER2-low breast cancer.

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 'in-field' skin toxicity in head and neck cancer patients treated with combined cetuximab and radiotherapy.

It is well known that the cetuximab (Cet) epidermal growth factor receptor (EGFR) antibody enhances the sensitivity of tumour cells to radiation, and it is likely that the concurrent administration of Cet and radiotherapy (RT) results in some degree of interplay between the effects of the individual agents on the skin and in the exacerbation of reactions normally seen with these individual agents. In this paper, we present a concise review of Cet/RT-related skin toxicity, focusing on mechanisms and pathogenesis, clinical presentation and scoring systems and, finally, therapeutic management.

Strategies for non-resectable head and neck cancer.

OPINION STATEMENT: Treatment of unresectable, locally advanced head and neck cancer consists of many different options, all of them based on radiotherapy. The main variable is represented by chemotherapy, i.e., the way in which chemotherapy is combined with radiation. More recently, the combination of cetuximab and radiotherapy emerged as a new treatment opportunity and induction chemotherapy, with the combination of docetaxel, cisplatin, and 5-fluoruracil, gained a renewed interest. Concurrent chemoradiation is based on the most robust evidence and is regarded as the leading standard of care for unresectable locally advanced head and neck cancer. Unfortunately, chemoradiation is hampered by severe toxicity and patients must be selected carefully before treatment. The experience of the staff (medical oncologists, radiation oncologists, and nurses), and in particular its familiarity with toxicity management, as well the structural facilities, play an important role in the final outcome. When the patient is unfit for chemoradiation, or when experienced staff or adequate structures are unavailable, induction chemotherapy, cetuximab and radiotherapy, or radiotherapy alone are all evidence-based alternative options. The choice among them will be based on the clinical condition of the patient, the physician's experience, and the patient's preference. Whatever is the treatment of choice, it is important to involve a multidisciplinary staff in the management of these patients. Indeed, also unresectable patients may require supportive surgical interventions before or during treatment, or removal of residual disease after treatment.

CDK4/6 inhibitors in the treatment of metastatic breast cancer: Focus on toxicity and safety.

The development of oral cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, including palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for patients with hormone-receptor-positive (HR+) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (BC). When combined with an aromatase inhibitor or fulvestrant, these agents have been approved as first-line therapy in the metastatic setting. Abemaciclib has also gained FDA approval for patients with HR-positive, HER2-negative, node-positive, early BC at high risk of recurrence. Moreover, ribociclib has recently improved disease-free survival in patients with stage II or III HR+/HER2-negative early BC. CDK4/6 inhibitors have favorable safety profiles. However, the available agents have different toxicity profiles that must be clearly discussed with the patients for optimal clinical decisions. This manuscript aims to review CDK4/6 inhibitor-related treatment-associated adverse events, identify risk factors for intolerable adverse events, and assess their safety in special patient populations such as the elderly and those with renal insufficiency. Enhanced knowledge and understanding of CDK4/6 inhibitor-related toxicities can improve treatment strategies and ultimately enhance patient care.

Baseline Cytokine Profile Identifies a Favorable Outcome in a Subgroup of Colorectal Cancer Patients Treated with Regorafenib.

Metastatic colorectal cancer is frequently associated with poor clinical conditions that may limit therapeutic options. Regorafenib is a small molecule approved for the treatment of metastatic colorectal cancer, but it is hampered by significative toxicities. Moreover, only a relatively limited number of patients benefit from the treatment. Therefore, the identification of reliable markers for response is an unmet need. Eighteen cytokines, selected based on their prevalent Th1 or Th2 effects, were collected. Peripheral blood samples were gathered at baseline in 25 metastatic colorectal cancer patients treated with regorafenib. Data extracted have been linked to progression-free survival. ROC identified the best cytokines associated with outcome. The relative value of the selected cytokines was determined by PCA. Data analysis identified 8 cytokines (TGF-ß, TNF-α, CCL-2, IL-6, IL-8, IL-10, IL-13 and IL-21), used to create a signature (TGF-ß, TNF-α high; CCL-2, IL-6, IL-8, IL-10, IL-13 and IL-21 low) corresponding to patients with a significantly longer progression-free survival. This report suggests that the analysis of multiple cytokines might identify a cytokine signature related to a patient's outcome that is able to recognize patients who will benefit from treatment. If confirmed, future studies, also based on different drugs, using this approach and including larger patient populations, might identify a signature allowing the a priori identification of patients to be treated.

Sonidegib in Locally Advanced Basal Cell Carcinoma: A Monocentric Retrospective Experience and a Review of Published Real-Life Data.

Basal cell carcinoma (BCC) represents the most common skin cancer and locally advanced BCC (laBCC) refers to an aggressive, large, infiltrative BCC that cannot be treated by surgery or radiotherapy. Sonidegib is a Hedghehog inhibitor (HHi) indicated for laBCC. This is a monocentric retrospective real-life study of laBCCs receiving Sonidegib treatment. Although Sonidegib is widely used, since its approval by Food and Drug Administration in 2015, only a limited number of real-life experiences have been reported. Eleven patients, including four patients diagnosed with Basal Cell Naevus syndrome, received treatment with Sonidegib for laBCCs. Seven (63.6%) patients experienced adverse events (AEs) but only three had to discontinue treatment and were therefore excluded from the following results. Four patients (50%) achieved complete clinical remission (CR); in all cases the remission was confirmed by biopsy. Partial response (PR) was found in three patients out of eight (37.5%). One patient out of eight (12.5%) showed a steady disease (SD). None of the patients showed signs of progression during treatment with HHi. Sonidegib showed the same efficacy in treating laBCCs as already seen in trials. All four patients suffering from Basal Cell Naevus syndrome achieved disease control by being treated with Sonidegib. Consequently, we strongly advise the joint management of laBCCs through a multidisciplinary team whenever feasible.

Anti-Claudin Treatments in Gastroesophageal Adenocarcinoma: Mainstream and Upcoming Strategies.

Claudins (CLDNs) are a multigene family of proteins and the principal components of tight junctions (TJs), which normally mediate cell-cell adhesion and selectively allow the paracellular flux of ions and small molecules between cells. Downregulation of claudin proteins increases the paracellular permeability of nutrients and growth stimuli to malignant cells, which aids the epithelial transition. Claudin 18.2 (CLDN18.2) was identified as a promising target for the treatment of advanced gastroesophageal adenocarcinoma (GEAC), with high levels found in almost 30% of metastatic cases. CLDN18.2 aberrations, enriched in the genomically stable subgroup of GEAC and the diffuse histological subtype, are ideal candidates for monoclonal antibodies and CAR-T cells. Zolbetuximab, a highly specific anti-CLDN18.2 monoclonal antibody, demonstrated efficacy in phase II studies and, more recently, in the phase III SPOTLIGHT trial, with improvements in both PFS and OS with respect to standard chemotherapy. Anti-CLDN18.2 chimeric antigen receptor (CAR)-T cells showed a safety profile with a prevalence of hematologic toxicity in early phase clinical trials. The aim of this review is to present new findings in the treatment of CLDN18.2-positive GEAC, with a particular focus on the monoclonal antibody zolbetuximab and on the use of engineered anti-CLDN18.2 CAR-T cells.