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New Approaches in the Management of Head and Neck Cancer

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (1 April 2021) | Viewed by 27989

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Prof. Dr. Patrick J. Schuler

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Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, Frauensteige 12, 89075 Ulm, Germany
Interests: head and neck cancer; immunotherapy, oncology;

Special Issue Information

Dear Colleagues,

Head and neck cancers are a heterogeneous group of malignant tumors, which often lead to dysphagia, dyspnea, and death. In the past, we have learned that head and neck cancers are not only caused by alcohol and tobacco but also by infection with the human papillomavirus. With the approval of PD1-inhibitors five years ago, the therapeutic approach to head and neck cancers has been reorganized in the palliative setting. Moreover, clinical studies for checkpoint inhibitors in the curative setting are on their way. However, the main challenge for the scientific community seems to be the identification of robust biomarkers. While the main focus is currently on checkpoint inhibitors, other fields of tumor immunology profit from this hype and may soon find their way into clinical routine. This includes vaccination trials, exosomes, liquid biopsies, or targeted therapy. In all cases, the timing and the right combination of therapeutic regimens, including surgery, radiation, chemotherapy, and immunotherapy, may be of great importance. In this Special Issue, experts in this field will review current approaches to the management of patients with head and neck cancers.

Prof. Dr. Patrick J. Schuler
Guest Editor

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Keywords

head and neck cancer
HNSCC
immunotherapy
oncology
checkpoint inhibitors
exosomes
liquid biopsy
targeted therapy
molecules
surgery
radiation
chemotherapy
biomarkers
prognosis
microenvironment
immune cells
HPV
PD-1
clinical trials

Published Papers (9 papers)

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Research

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19 pages, 6076 KiB

Open AccessArticle

Possible Therapeutic Strategy Involving the Purine Synthesis Pathway Regulated by ITK in Tongue Squamous Cell Carcinoma

by Kaoru Onidani, Nami Miura, Yuki Sugiura, Yuichi Abe, Yukio Watabe, Takanori Kakuya, Taisuke Mori, Seiichi Yoshimoto, Jun Adachi, Takao Kiyoi, Yasuaki Kabe, Makoto Suematsu, Takeshi Tomonaga, Takahiko Shibahara and Kazufumi Honda

Cancers 2021, 13(13), 3333; https://doi.org/10.3390/cancers13133333 - 2 Jul 2021

Cited by 3 | Viewed by 2822

Abstract

The epidermal growth factor receptor is the only available tyrosine kinase molecular target for treating oral cancer. To improve the prognosis of tongue squamous cell carcinoma (TSCC) patients, a novel molecular target for tyrosine kinases is thus needed. We examined the expression of interleukin-2–inducible T-cell kinase (ITK) using immunohistochemistry, and the biological function of ITK was investigated using biochemical, phosphoproteomic, and metabolomic analyses. We found that ITK is overexpressed in TSCC patients with poor outcomes. The proliferation of oral cancer cell lines expressing ITK via transfection exhibited significant increases in three-dimensional culture assays and murine inoculation models with athymic male nude mice as compared with mock control cells. Suppressing the kinase activity using chemical inhibitors significantly reduced the increase in cell growth induced by ITK expression. Phosphoproteomic analyses revealed that ITK expression triggered phosphorylation of a novel tyrosine residue in trifunctional purine biosynthetic protein adenosine-3, an enzyme in the purine biosynthesis pathway. A significant increase in de novo biosynthesis of purines was observed in cells expressing ITK, which was abolished by the ITK inhibitor. ITK thus represents a potentially useful target for treating TSCC through modulation of purine biosynthesis. Full article

(This article belongs to the Special Issue New Approaches in the Management of Head and Neck Cancer)

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15 pages, 4814 KiB

Open AccessArticle

B-Helper Neutrophils in Regional Lymph Nodes Correlate with Improved Prognosis in Patients with Head and Neck Cancer

by Ekaterina Pylaeva, Irem Ozel, Anthony Squire, Ilona Spyra, Charlotte Wallner, Magdalena Korek, Georg Korschunow, Maksim Domnich, Elena Siakaeva, Moritz Goetz, Agnes Bankfalvi, Stephan Lang, Benjamin Kansy and Jadwiga Jablonska

Cancers 2021, 13(12), 3092; https://doi.org/10.3390/cancers13123092 - 21 Jun 2021

Cited by 6 | Viewed by 2536

Abstract

The role of neutrophils during cancer formation and elimination is diverse. Here, for the first time, we investigate neutrophil helper cells (N_BH), their influence on B cell activity in the regional lymph nodes (RLN) of head-and-neck cancer patients and the effect of this neutrophil/B cell interaction on patient prognosis. Circulating and RLN neutrophils of patients with stage I–IV head-and-neck squamous cell carcinoma were investigated with flow cytometry and qPCR. In addition, neutrophil/B cell co-localization in RLNs was evaluated using immunohistochemistry. B cell proliferation was assessed and correlated with the distance to neutrophils. Patient survival was evaluated. Neutrophils with the helper cell phenotype were identified in the RLN of HNC patients. B cells in close proximity to such N_BH showed significantly higher proliferation rates, together with elevated activation-induced cytidine deaminase (AID) expression. Notably, patient survival was significantly higher in individuals with high N_BH frequencies in the B follicles of RLNs. Neutrophils in RLN can support T cell-independent activation of the adaptive immune system through B cell stimulation, capturing helper cell phenotype character. The presence of such helper neutrophils in the RLNs of HNC patients positively correlates with patient prognosis. Full article

(This article belongs to the Special Issue New Approaches in the Management of Head and Neck Cancer)

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12 pages, 690 KiB

Open AccessArticle

Implementation of Double Immune Checkpoint Blockade Increases Response Rate to Induction Chemotherapy in Head and Neck Cancer

by Sabine Semrau, Antoniu-Oreste Gostian, Maximilian Traxdorf, Markus Eckstein, Sandra Rutzner, Jens von der Grün, Thomas Illmer, Matthias Hautmann, Gunther Klautke, Simon Laban, Thomas Brunner, Bálint Tamaskovics, Benjamin Frey, Jian-Guo Zhou, Carol-Immanuel Geppert, Arndt Hartmann, Panagiotis Balermpas, Wilfried Budach, Udo Gaipl, Heinrich Iro, Rainer Fietkau and Markus Hecht Show full author list Hide full author list

Cancers 2021, 13(8), 1959; https://doi.org/10.3390/cancers13081959 - 19 Apr 2021

Cited by 12 | Viewed by 2476

Abstract

To determine whether a single dose of double immune checkpoint blockade (induction chemoimmunotherapy (ICIT)) adds benefit to induction single-cycle platinum doublet (induction chemotherapy (IC)) in locally advanced head and neck squamous cell carcinoma (HNSCC), patients treated with cisplatin 30 mg/m² d1-3 and docetaxel 75 mg/m² d1 combined with durvalumab 1500 mg fixed dose d5 and tremelimumab 75 mg fixed dose d5 (ICIT) within the CheckRad-CD8 trial were compared with a retrospective cohort receiving the same chemotherapy (IC) without immunotherapy. The endpoint of this analysis was the complete response rate (CR). A total of 53 patients were treated with ICIT and 104 patients with IC only. CR rates were 60.3% for ICIT and 40.3% for IC (p = 0.018). In the total population (n = 157), the most important predictor to achieve a CR was treatment type (OR: 2.21 for ICIT vs. IC; p = 0.038, multivariate analysis). The most diverse effects in CR rates between ICIT and IC were observed in younger (age ≤ 60) patients with HPV-positive OPSCCs (82% vs. 33%, p = 0.176), while there was no difference in older patients without HPV-positive OPSCCs (53% vs. 48%). The analysis provides initial evidence that ICIT could result in higher CR rates than IC. Young patients with HPV-positive OPSCCs may have the greatest benefit from additional immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue New Approaches in the Management of Head and Neck Cancer)

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16 pages, 1742 KiB

Open AccessArticle

Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker

by Ximena Terra, Victoria Ceperuelo-Mallafré, Carla Merma, Ester Benaiges, Ramon Bosch, Paola Castillo, Joan Carles Flores, Xavier León, Izaskun Valduvieco, Neus Basté, Marina Cámara, Marylène Lejeune, Josep Gumà, Joan Vendrell, Isabel Vilaseca, Sonia Fernández-Veledo and Francesc Xavier Avilés-Jurado

Cancers 2021, 13(7), 1653; https://doi.org/10.3390/cancers13071653 - 1 Apr 2021

Cited by 15 | Viewed by 3450

Abstract

Head and neck squamous cell carcinoma (HNSCC) is characterized by high rates of mortality and treatment-related morbidity, underscoring the urgent need for innovative and safe treatment strategies and diagnosis practices. Mitochondrial dysfunction is a hallmark of cancer and can lead to the accumulation of tricarboxylic acid cycle intermediates, such as succinate, which function as oncometabolites. In addition to its role in cancer development through epigenetic events, succinate is an extracellular signal transducer that modulates immune response, angiogenesis and cell invasion by activating its cognate receptor SUCNR1. Here, we explored the potential value of the circulating succinate and related genes in HNSCC diagnosis and prognosis. We determined the succinate levels in the serum of 66 pathologically confirmed, untreated patients with HNSCC and 20 healthy controls. We also surveyed the expression of the genes related to succinate metabolism and signaling in tumoral and nontumoral adjacent tissue and in normal mucosa from 50 patients. Finally, we performed immunohistochemical analysis of SUCNR1 in mucosal samples. The results showed that the circulating levels of succinate were higher in patients with HNSCC than in the healthy controls. Additionally, the expression of SUCNR1, HIF-1α, succinate dehydrogenase (SDH) A, and SDHB was higher in the tumor tissue than in the matched normal mucosa. Consistent with this, immunohistochemical analysis revealed an increase in SUCNR1 protein expression in tumoral and nontumoral adjacent tissue. High SUCNR1 and SDHA expression levels were associated with poor locoregional control, and the locoregional recurrence-free survival rate was significantly lower in patients with high SUCNR1 and SDHA expression than in their peers with lower levels (77.1% [95% CI: 48.9–100.0] vs. 16.7% [95% CI: 0.0–44.4], p = 0.018). Thus, the circulating succinate levels are elevated in HNSCC and high SUCNR1/SDHA expression predicts poor locoregional disease-free survival, identifying this oncometabolite as a potentially valuable noninvasive biomarker for HNSCC diagnosis and prognosis. Full article

(This article belongs to the Special Issue New Approaches in the Management of Head and Neck Cancer)

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20 pages, 6379 KiB

Open AccessArticle

Immune-Stimulatory Effects of Curcumin on the Tumor Microenvironment in Head and Neck Squamous Cell Carcinoma

by Charlotte Kötting, Linda Hofmann, Ramin Lotfi, Daphne Engelhardt, Simon Laban, Patrick J. Schuler, Thomas K. Hoffmann, Cornelia Brunner and Marie-Nicole Theodoraki

Cancers 2021, 13(6), 1335; https://doi.org/10.3390/cancers13061335 - 16 Mar 2021

Cited by 14 | Viewed by 2948

Abstract

Curcumin is known to have immune-modulatory and antitumor effects by interacting with more than 30 different proteins. An important feature of curcumin is the inhibition of nuclear factor kappa of activated B-cells (NF-κB). Here, we evaluate the potential of curcumin to reverse the epithelial to mesenchymal transition (EMT) of head and neck squamous cell carcinoma (HNSCC) cells as a part of tumor escape mechanisms. We examined the impact of curcumin on the expression of different pro- and antitumoral chemokines in ex vivo HNSCC tumor tissue and primary macrophage cultures. Further, we evaluated the combinatorial effect of curcumin and toll-like receptor 3 (TLR3) agonist Poly I:C (PIC) on NF-κB inhibition and regulatory T-cell (Treg) attraction. Mesenchymal markers were significantly reduced in cancer specimens after incubation with curcumin, with simultaneous reduction of key transcription factors of EMT, Snail, and Twist. Furthermore, a decrease of the Treg-attracting chemokine CCL22 was observed. Additionally, curcumin-related inhibition of NF-κB nuclear translocation was evident. The combination of PIC with curcumin resulted in further NF-κB inhibition, whereas PIC alone contrarily resulted in NF-κB activation. Furthermore, curcumin was more effective in inhibiting PIC-dependent NF-κB activation and Treg attraction compared to known NF-κB inhibitors BAY 11-7082 or caffeic acid phenethyl ester (CAPE). The presented results show, for the first time, the immune-modulating effects of curcumin in HNSCC, with potent inhibition of the Treg-attracting effects of PIC. Hence, curcumin presents a promising drug in cancer therapy as a supplement to already established treatments. Full article

(This article belongs to the Special Issue New Approaches in the Management of Head and Neck Cancer)

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10 pages, 2028 KiB

Open AccessArticle

Increasing Mean Age of Head and Neck Cancer Patients at a German Tertiary Referral Center

by Julius M. Vahl, Marlene C. Wigand, Michael Denkinger, Dhayana Dallmeier, Chiara Steiger, Claudia Welke, Peter Kuhn, Christian Idel, Johannes Doescher, Adrian von Witzleben, Matthias Brand, Ralf Marienfeld, Peter Möller, Marie-Nicole Theodoraki, Jens Greve, Patrick J. Schuler, Cornelia Brunner, Thomas K. Hoffmann and Simon Laban

Cancers 2021, 13(4), 832; https://doi.org/10.3390/cancers13040832 - 17 Feb 2021

Cited by 13 | Viewed by 2200

Abstract

Background: The impact of demographic change on the age at diagnosis in German head and neck cancer (HNC) patients is unclear. Here we present an evaluation of aging trends in HNC at a tertiary referral center. Methods: Retrospective cohort study on aging trends at the initial diagnosis of newly diagnosed patients with HNC between 2004 and 2018 at the head and neck cancer center Ulm in relation to demographic data of the catchment area. Results: The study population consisted of 2450 individuals diagnosed with HNC with a mean age of 62.84 (±11.67) years. We observed a significant increase in annual incidence rates and mean age over time. Mean age among HNC patients increased significantly more than among the population in the catchment area. Whereas the incidence rate of patients <50 years did not change, the incidence of HNC patients aged ≥70 years increased the most. The mean patient age in the main tumor sites increased significantly. Surprisingly, HPV-positive patients were not younger than HPV-negative patients, but showed a non-significant trend towards a higher mean age (63.0 vs. 60.7 years). Conclusions: Increasing incidence rates in older patients pose a challenge for health care systems. A nationwide study is needed to assess the dynamics and impact of aging on the incidence of HNC. Full article

(This article belongs to the Special Issue New Approaches in the Management of Head and Neck Cancer)

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19 pages, 2108 KiB

Open AccessArticle

Growth Factor Receptor Expression in Oropharyngeal Squamous Cell Cancer: Her1–4 and c-Met in Conjunction with the Clinical Features and Human Papillomavirus (p16) Status

by Eric Deuss, Dorothee Gößwein, Désirée Gül, Stefanie Zimmer, Sebastian Foersch, Claudia S. Eger, Ivonne Limburg, Roland H. Stauber and Julian Künzel

Cancers 2020, 12(11), 3358; https://doi.org/10.3390/cancers12113358 - 13 Nov 2020

Cited by 5 | Viewed by 2175

Abstract

This study aimed to assess the distribution of growth factor receptors in oropharyngeal squamous cell cancer (OPSCC) and evaluate their role in the context of human papillomavirus (HPV) status, prognosis and potential relevance for targeted therapy. The protein expression of human epidermal growth factor receptor (Her)1–4 and c-Met were retrospectively assessed using semiquantitative immunohistochemistry on tissue microarrays and analyzed for correlations as well as differences in the clinicopathological criteria. Her1–4 and c-met were overexpressed compared to normal mucosa in 46%, 4%, 17%, 27% and 23%, respectively. Interestingly, most receptors were coexpressed. Her1 and c-Met were inversely correlated with p16 (p = 0.04; p = 0.02). Her2 and c-Met were associated with high tobacco consumption (p = 0.016; p = 0.04). High EGFR, Her3, Her4 and c-Met expression were associated with worse overall and disease-free survival (p ≤ 0.05). Furthermore, EGFR and c-Met expression showed raised hazard ratios of 2.53 (p = 0.02; 95% CI 1.24–5.18) and 2.45 (p = 0.02; 95% CI 1.13–5.35), respectively. Her4 was expressed less in distant metastases than in corresponding primary tumors and was correlated to a higher T category. EGFR and c-Met are relevant negative prognostic factors in OPSCC, independent of known clinicopathological parameters. We suggest dual targeting of EGFR and c-Met as a promising strategy for OPSCC treatment. Full article

(This article belongs to the Special Issue New Approaches in the Management of Head and Neck Cancer)

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Review

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24 pages, 1639 KiB

Open AccessReview

Immuno-Oncological Biomarkers for Squamous Cell Cancer of the Head and Neck: Current State of the Art and Future Perspectives

by Stijn J. De Keukeleire, Tijl Vermassen, Elien Hilgert, David Creytens, Liesbeth Ferdinande and Sylvie Rottey

Cancers 2021, 13(7), 1714; https://doi.org/10.3390/cancers13071714 - 4 Apr 2021

Cited by 15 | Viewed by 3381

Abstract

The era of immune checkpoint inhibitors has altered the therapeutic landscape in squamous cell cancer of the head and neck (SCCHN). Our knowledge about the tumor microenvironment has fueled the research in SCCHN, leading to several well-known and less-known prognostic and predictive biomarkers. The clinical staging, p16/HPV status, and PD-L1 expression are currently the main tools for assessing the patients’ diagnosis and prognosis. However, several novel biomarkers have been thoroughly investigated, some reaching actual significant clinical contributions. The untangling of the immune infiltrate with the subtyping of tissue-associated tumor infiltrating lymphocytes, tumor-associated macrophages, and circulating blood-based biomarkers are an interesting avenue to be further explored and prospectively assessed. Although PD-L1 expression remains the most important response predictor for immune checkpoint inhibitors, several flaws impede proper assessment such as technical issues, different scoring protocol, and intra-, inter-, and temporal heterogeneity. In addition, the construction of an immune-related gene panel has been proposed as a prognostic and predictive stratification but lacks consensus. Recently, the role of microbioma have also been explored regarding its systemic and antitumor immunity. This review gives a comprehensive overview of the aforementioned topics in SCCHN. To this end, the integration of these clinically advantageous biomarkers via construction of an immunogram or nomogram could be an invaluable tool for SCCHN in future prospects. Full article

(This article belongs to the Special Issue New Approaches in the Management of Head and Neck Cancer)

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17 pages, 2471 KiB

Open AccessSystematic Review

Current Advances in Robotics for Head and Neck Surgery—A Systematic Review

by Felix Boehm, Rene Graesslin, Marie-Nicole Theodoraki, Leon Schild, Jens Greve, Thomas K. Hoffmann and Patrick J. Schuler

Cancers 2021, 13(6), 1398; https://doi.org/10.3390/cancers13061398 - 19 Mar 2021

Cited by 15 | Viewed by 4811

Abstract

Background. In the past few years, surgical robots have recently entered the medical field, particularly in urology, gynecology, and general surgery. However, the clinical effectiveness and safety of robot-assisted surgery (RAS) in the field of head and neck surgery has not been clearly established. In this review, we evaluate to what extent RAS can potentially be applied in head and neck surgery, in which fields it is already daily routine and what advantages can be seen in comparison to conventional surgery. Data sources. For this purpose, we conducted a systematic review of trials published between 2000 and 2021, as well as currently ongoing trials registered in clinicaltrials.gov. The results were structured according to anatomical regions, for the topics “Costs,” “current clinical trials,” and “robotic research” we added separate sections for the sake of clarity. Results. Our findings show a lack of large-scale systematic randomized trials on the use of robots in head and neck surgery. Most studies include small case series or lack a control arm which enables a comparison with established standard procedures. Conclusion. The question of financial reimbursement is still not answered and the systems on the market still require some specific improvements for the use in head and neck surgery. Full article

(This article belongs to the Special Issue New Approaches in the Management of Head and Neck Cancer)

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