Essential data variables for a minimum dataset for head and neck cancer trials and clinical research: HNCIG consensus recommendations and database.

The Head and Neck Cancer International Group (HNCIG) has undertaken an international modified Delphi process to reach consensus on the essential data variables to be included in a minimum database for HNC research. Endorsed by 19 research organisations representing 34 countries, these recommendations provide the framework to facilitate and harmonise data collection and sharing for HNC research. These variables have also been incorporated into a ready to use downloadable HNCIG minimum database, available from the HNCIG website.

Baseline Values of Circulating IL-6 and TGF-ß Might Identify Patients with HNSCC Who Do Not Benefit from Nivolumab Treatment.

BACKGROUND: The immunotherapy of head and neck cancer induces a limited rate of long-term survivors at the cost of treating many patients exposed to toxicity without benefit, regardless of PD-L1 expression. The identification of better biomarkers is warranted. We analyzed a panel of cytokines, chemokines and growth factors, hereinafter all referred to as 'cytokines', as potential biomarkers in patients with head and neck cancer treated with nivolumab. MATERIALS AND METHODS: A total of 18 circulating cytokines were analyzed. Samples were gathered at baseline (T0) and after 3 courses of nivolumab (T1) in patients with relapsed/metastatic disease. The data extracted at T0 were linked to survival; the comparison of T0-T1 explored the effect of immunotherapy. RESULTS: A total of 22 patients were accrued: 64% current heavy smokers, 36% female and 14% had PS = 2. At T0, ROC analysis showed that IL-6, IL-8, IL-10 and TGF-ß were higher in patients with poor survival. Cox analysis demonstrated that only patients with the IL-6 and TGF-ß discriminate had good or poor survival, respectively. Longitudinal increments of CCL-4, IL-15, IL-2 and CXCL-10 were observed in all patients during nivolumab treatment. CONCLUSION: In this small population with poor clinical characteristics, this study highlights the prognostic role of IL-6 and TGF-ß. Nivolumab treatment is associated with a positive modulation of some Th1 cytokines, but it does not correlate with the outcome.

The oligometastatic setting in HNSCC: A critical review by the Rete Oncologica Piemonte e Valle d'Aosta multidisciplinary team.

INTRODUCTION: The oligometastatic disease is a low burden metastatic disease that might still benefit from curable treatment. Squamous cell carcinoma of the head and neck (HNSCC) is a complex group of malignancies, with high rates of loco-regional recurrences. Distant metastases are less frequent, and a single or few deposits are often observed (oligometastatic disease). The optimal management of oligometastatic HNSCC remains to be defined. MATERIALS AND METHODS: Key references were derived from a PubMed query. Hand searching and clinicaltrials.gov were also used. RESULTS: This paper contains a narrative report and a critical discussion of the available evidence on the management of oligometastatic HNSCC patients, with a focus on metastasis-directed therapy (MDT), particularly stereotactic ablative radiotherapy (SABR). CONCLUSIONS: in line with literature data, the multidisciplinary evaluation emerged as the key element in the management of oligometastatic HNSCC patients.

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.

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.

Thrombotic Events during Lenvatinib Treatment: A Single Institution Experience.

Lenvatinib is the standard treatment for radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thromboembolic (TE) side effects are quite rare (1-3% of treated patients) in clinical trials. Nevertheless, patients with predisposing factors are at a higher risk of developing cardiovascular adverse events. Reduction of lenvatinib starting dose and cardiologic counselling to provide appropriate supportive therapies are usually recommended for high-risk patients. From 2016 to 2022, we analyzed a series of 16 patients who were consecutively treated at our institution. All except one patient received a reduction in their dosage after two cycles of therapy because of toxicities, and four patients (25%) suffered from TE. The observed incidence in our patient sample seemed to be higher than expected. We hypothesized that our patient sample might be at higher risk probably because of the heavy prior loco-regional treatments performed.

The Role of Cytokinome in the HNSCC Tumor Microenvironment: A Narrative Review and Our Experience.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer. In locally advanced (LA) HNSCC, a multidisciplinary approach consisting of surgery followed by chemoradiation (CRT) or definitive CRT is the mainstay of treatment. In recurrent metastatic (R/M), HNSCC immune checkpoint inhibitors (ICIs) with or without chemotherapy represent the new first-line option. However, cancer will recur in about two out of five patients with LA HNSCC. If progression occurs within six months from platin-radiotherapy treatment, anti-programmed cell death-1 (PD-1) may be prescribed. Otherwise, immunotherapy with or without chemotherapy might be considered if PD-L1 is expressed. Despite several improvements in the outcome of patients with R/M HNSCC, overall survival (OS) remains dismal, equaling a median of 14 months. In-depth knowledge of the tumor microenvironment (TME) would be required to change the course of this complex disease. In recent years, many predictive and prognostic biomarkers have been studied in the HNSCC TME, but none of them alone can select the best candidates for response to ICIs or targeted therapy (e.g., Cetuximab). The presence of cytokines indicates an immune response that might occur, among other things, after tumor antigen recognition, viral and bacterial infection, and physic damage. An immune response against HNSCC results in the production of some cytokines that induce a pro-inflammatory response and attract cells, such as neutrophils, macrophages, and T cell effectors, to enhance the innate and adaptive anti-tumor response. We revised the role of a group of cytokines as biomarkers for treatment response in HNSCC.

How Risk Factors Affect Head and Neck Squamous Cell Carcinoma (HNSCC) Tumor Immune Microenvironment (TIME): Their Influence on Immune Escape Mechanisms and Immunotherapy Strategy.

Most head and neck squamous cell carcinomas (HNSCCs) are caused by lifestyle, such as cigarette smoking, or by viruses, such as human papillomavirus (HPV) and Epstein-Barr virus (EBV). HNSCC remains a clinical challenge, notwithstanding the improvements observed in the past years, involving surgery, radiotherapy, and chemotherapy. Recurrent/metastatic (R/M) disease represents an unmet clinical need. Immunotherapy has improved the prognosis of a small proportion of these patients, but most still do not benefit. In the last decade, several preclinical and clinical studies have explored the HNSCC tumor immune microenvironment (TIME), identifying important differences between smoking-associated and virus-associated HNSCCs. This review aims to present how different etiologies affect the HNSCC TIME, affecting immune escape mechanisms and sensitivity to immunotherapy.

How Chemotherapy Affects the Tumor Immune Microenvironment: A Narrative Review.

Chemotherapy is much more effective in immunocompetent mice than in immunodeficient ones, and it is now acknowledged that an efficient immune system is necessary to optimize chemotherapy activity and efficacy. Furthermore, chemotherapy itself may reinvigorate immune response in different ways: by targeting cancer cells through the induction of cell stress, the release of damage signals and the induction of immunogenic cell death, by targeting immune cells, inhibiting immune suppressive cells and/or activating immune effector cells; and by targeting the host physiology through changes in the balance of gut microbiome. All these effects acting on immune and non-immune components interfere with the tumor microenvironment, leading to the different activity and efficacy of treatments. This article describes the correlation between chemotherapy and the immune changes induced in the tumor microenvironment. Our ultimate aim is to pave the way for the identification of the best drugs or combinations, the doses, the schedules and the right sequences to use when chemotherapy is combined with immunotherapy.

A narrative review of the principal glucocorticoids employed in cancer.

Glucocorticoids (GCs) are a pharmacological class of drugs widely used in oncology in both supportive and palliative settings. GCs differentially impact organs with immediate and long-term effects; with suppressive effect on the immune system anchoring their use to manage the toxicities of immune checkpoint inhibitors (ICIs). In addition, GCs are often used in the management of symptoms related to cancer or chemotherapy and as adjuvants in the treatment of pain in the management of other. In the palliative setting, GCs, especially administered subcutaneously can be to assist in the control of nausea, dyspnea, asthenia, and anorexia-cachexia syndrome. In this narrative review, we aim to summarize the role of GCs in the different settings (curative, supportive, and palliative) to help clinicians use these important drugs in their daily clinical practice with cancer patients.

Anti-PD-1 and Anti-PD-L1 in Head and Neck Cancer: A Network Meta-Analysis.

Objective: The monoclonal antibodies anti-programmed death protein-1 (anti-PD-1) nivolumab and pembrolizumab are the first immune checkpoint inhibitors (ICIs) approved for treatment of recurrent/metastatic head and neck carcinoma R/M HNSCC in first line and in platinum refractory disease. This network meta-analysis aims to investigate the efficacy of anti-PD-1- vs anti-PD-L1-based therapy in R/M HNSCC cancer patients through a systematic review of the literature to provide support for evidence-based treatment decisions. In particular, the effectiveness of ICIs for R/M HNSCC is analyzed according to the different mechanisms of action of the check-points inhibitory drugs in different subgroups of patients. Methods: We did a systematic literature review and network meta-analysis (NMA) of randomized controlled trials (RCTs) in PubMed, ClinicalTrials.gov, Embase, Medline, the Cochrane Central Register of Controlled Trials, Web of Science. Our search identified a total of five randomized controlled trials: Keynote 040, Keynote 048, Eagle, Condor, Checkmate 141. These trials included 3001 patients. Treatment was sub-categorized into PD-L1-based, PD-1-based, and standard chemotherapy. Treatments were indirectly compared with anti-PD-L1-based therapy. Results: The network meta-analysis demonstrated no significant differences in OS between different subgroups except for the metastatic patients in which anti-PD-1-based therapy was associated with significantly less risk of death. Furthermore, anti-PD-1-based therapy appeared to be effective in smoker patients and in human papilloma-negative (HPV) patients. Conversely, anti-PD-L1-based therapy seems to be better efficient in female patients, in locally recurrent setting and in HPV positive patients. Conclusion: This is the first NMA study that aimed to indirectly compare anti-PD-1- and anti-PD-L1-based therapy in HNSCC patients. The results of our NMA could help define a profile of patient responder or resistant to specific classes of immune drugs and can be used to guide/design future studies in the novel scenario of precision immune-oncology.

Unusual Fatal Outcome Following Administration of a Combination of anti-PD1 and anti-CTLA4 in Metastatic Renal Cell Carcinoma: Liver Toxicity Case Report and a Literature Review.

Hepatic dysfunction, in the absence of liver metastases, occurs in 10-15% of renal cell carcinoma (RCC) patients, while immune hepatitis due to anti-CTLA4 and anti-PD1 administration affects about 3-9% and 0.7-1.8% of treated patients, respectively. Liver toxicity following combination therapy (anti-CTLA4 and anti-PD1) is seen in 29% of patients overall and grade 3-4 toxicity in 14% of patients. Stauffer's syndrome is a rare para-neoplastic phenomenon associated with RCC and characterized by abnormal liver function tests, hepato-splenomegaly and histological changes consistent with non-specific hepatitis. We describe a case of RCC treated with anti-CTLA4 and anti-PD1 therapy resulting in immediate liver toxicity and death after 2 months of progressive hepatic impairment. We hypothesize that high IL-6 levels due to Stauffer's syndrome might have contributed to immune-related hepatic failure. LEARNING POINTS: Consider Stauffer's syndrome in patients who develop liver toxicity unresponsive to immunotherapy.Evaluate IL-6 as high levels are seen in Stauffer's syndrome patients undergoing immunotherapy.Consider taking a liver biopsy to assess the severity of liver injury.

Further Understanding of the Immune Microenvironment in Head and Neck Squamous Cell Carcinoma: Implications for Prognosis.

PURPOSE: We aimed to review the literature on the tumor microenvironment as a key player in tumor growth and anti-cancer treatment responses in head and neck cancer. PATIENTS AND METHODS: We reviewed the recent literature on this topic, using the following research words: "tumor microenvironment" and "head and neck cancer or neoplasm or head and neck squamous cell carcinoma" and "immune cells" and "stromal cells". A search was conducted on the PubMed website and reports from international meetings, presentations and abstracts. RESULTS: The tumor microenvironment is a complex network in which myeloid cells, tumoral cells, growth factors and cytokines are involved in angiogenesis, the extracellular matrix and epithelial-to-mesenchymal transition. CONCLUSION: Immune resistance and rapid tumor growth depend on immunosuppressive and pro-tumoral environments. Further investigations to classify and adequately treat patients with head and neck cancer are required.

Cytokine Profiling of End Stage Cancer Patients Treated with Immunotherapy.

Published data suggest that immunotherapy plays a role even in patients with very advanced tumours. We investigated the immune profile of end-stage cancer patients treated with immunotherapy to identify changes induced by treatment. Breast, colon, renal and prostate cancer patients were eligible. Treatment consisted of metronomic cyclophosphamide, low-dose interleukin-2 (IL-2) and a single radiation shot. A panel of 16 cytokines was assessed using automated ELISA before treatment (T0), after radiation (RT; T1), at cycle 2 (T2) and at disease progression (TPD). Receiving operating characteristic (ROC) analysis was used to identify cytokine cut-off related to overall survival (OS). Principal component analysis (PCA) was used to identify the immune profile correlating better with OS and progression-free survival. Twenty-three patients were enrolled. High IL-2, low IL-8 and CCL-2 correlated with OS. The PCA identified a cluster of patients, with high IL-2, IL-12 and IFN-γ levels at T0 having longer PFS and OS. In all cohorts, IL-2 and IL-5 increased from T0 to T2; a higher CCL-4 level compared to T2 and a higher IL-8 level compared to T0 were found at TPD. The progressive increase of the IL-10 level during treatment negatively correlated with OS. Our data suggested that baseline cytokine levels may predict patients' outcome and that the treatment may affect their kinetic even in end-stage patients. Cytokine profiling of end-stage patients might offer a tool for medical decisions (EUDRACT: 2016-000578-39).

VEGF-Related Germinal Polymorphisms May Identify a Subgroup of Breast Cancer Patients with Favorable Outcome under Bevacizumab-Based Therapy-A Message from COMET, a French Unicancer Multicentric Study.

The prospective multicenter COMET trial followed a cohort of 306 consecutive metastatic breast cancer patients receiving bevacizumab and paclitaxel as first-line chemotherapy. This study was intended to identify and validate reliable biomarkers to better predict bevacizumab treatment outcomes and allow for a more personalized use of this antiangiogenic agent. To that end, we aimed to establish risk scores for survival prognosis dichotomization based on classic clinico-pathological criteria combined or not with single nucleotide polymorphisms (SNPs). The genomic DNA of 306 patients was extracted and a panel of 13 SNPs, covering seven genes previously documented to be potentially involved in drug response, were analyzed by means of high-throughput genotyping. In receiver operating characteristic (ROC) analyses, the hazard model based on a triple-negative cancer phenotype variable, combined with specific SNPs in VEGFA (rs833061), VEGFR1 (rs9582036) and VEGFR2 (rs1870377), had the highest predictive value. The overall survival hazard ratio of patients assigned to the poor prognosis group based on this model was 3.21 (95% CI (2.33-4.42); p < 0.001). We propose that combining this pharmacogenetic approach with classical clinico-pathological characteristics could markedly improve clinical decision-making for breast cancer patients receiving bevacizumab-based therapy.

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.

The Impact of Locoregional Treatment on Response to Nivolumab in Advanced Platinum Refractory Head and Neck Cancer: The Need Trial.

BACKGROUND: Previous locoregional treatment could affect the response to nivolumab in platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). The aim of this study is to evaluate the impact of the clinicopathological characteristics and previous treatment in predicting early progression to nivolumab in a real-world population. METHODS: This is an observational, multicenter retrospective/prospective study including patients (pts) with platinum refractory R/M HNSCC who received nivolumab 240 mg every 2 weeks from October 2018 to October 2019. We analyzed the association between previous treatment, clinicopathological characteristics, and early progression (within 3 months). RESULTS: Data from 61 pts were reviewed. Median age was 67 years (30-82). Forty-two pts (69%) received previous locoregional treatment. Early progression to nivolumab occurred in 36 pts (59%), while clinical benefit (stable disease and partial response) was achieved in 25 pts (41%). Early progression to nivolumab was significantly associated to previous locoregional treatment both at univariate and multivariate analysis (p = 0.005 and p = 0.048, respectively). CONCLUSION: nivolumab in R/M HNSCC is burdened with a high early progression rate. Previous wide neck dissection and high dose radiotherapy may compromise the efficacy of nivolumab, distorting the anatomy of the local lymphatic system and hindering the priming of immune response.

Circulating cytokines and outcome in metastatic colorectal cancer patients treated with regorafenib.

BACKGROUND: Regorafenib is an oral small-molecule multikinase inhibitor approved in third or later line of treatment for patients with metastatic colorectal cancer (mCRC). Regorafenib has shown significant benefits in overall survival and progression free survival in two phase III trials compared to placebo in patients with mCRC who had progressed on previous therapy. AIM: To identify an immune profile that might specifically correlate with the outcome in patients treated with regorafenib. METHODS: Blood samples were collected from 17 patients before treatment with regorafenib and from 6 healthy volunteers. The proteins evaluated (TNF-α, TGF-ß, VEGF, CCL-2, CCL-4, and CCL-5) were selected on the basis of their roles in angiogenesis and colorectal cancer pathogenesis. RESULTS: We found that TNF-α basal level was significantly higher in mCRC patients compared to healthy individuals. Non Responder (NR) patients showing progression of disease (n = 12) had higher basal level of TGF-ß, TNF-α, VEGF, CCL-2 and CCL-5 compared to Responder (R) patients (complete response CR, n = 1; partial response PR, n = 1; Stable Disease SD, n = 3). On the contrary, plasma basal level of CCL-4 was higher in R compared to NR patients. High values of TGF-ß and TNF-α negatively correlated with progression free survival. CONCLUSION: These results suggest a cytokine signature potentially able to discriminate between R and NR patients to treatment with regorafenib.