Influence of travel burden on tumor classification and survival of head and neck cancer patients.

PURPOSE: Cancer patients have to overcome various barriers to obtain diagnostics and treatment at head and neck cancer centers. Travel distance to a specialized hospital may result in psychosocial and financial distress, thus interfering with diagnostics, treatment, and follow-up care. In this study, we have aimed to analyze the association of travel distance with cTNM status, UICC stage at primary diagnosis, and survival outcomes of head and neck cancer (HNC) patients. METHODS: We have analyzed data of 1921 consecutive HNC patients diagnosed between 2014 and 2019 at the head and neck cancer center of the Comprehensive Cancer Center Ulm (CCCU), Germany. Postal code-based travel distance calculation in kilometers, TNM status, and UICC stage were recorded at initial diagnosis. The assembly of travel distance-related groups (short, intermediate, long-distance) has been investigated. Moreover, group-related survival and recurrence analysis have been performed. RESULTS: In contrast to observations from overseas, no association of travel distance and higher cTNM status or UICC stage at primary diagnosis has been observed. Furthermore, no significant differences for recurrence-free survival and overall survival by travel distance were detected. CONCLUSION: In southern Germany, travel distance to head and neck cancer centers seems to be tolerable. Travel burden is not synonymous with travel distance alone but also involves sociodemographic, monetary, and disease-specific aspects as well as accessibility to proper infrastructure of transport and health care system.

[Tumor biology of oropharyngeal carcinoma]. / Tumorbiologie des Oropharynxkarzinoms.

BACKGROUND: Etiologically, oropharyngeal squamous cell carcinoma (OPSCC) can be divided into OPSCC caused by noxious agents and human papillomavirus (HPV)-driven carcinoma. These types differ with regard to clinical features and prognosis-differences which are rooted in the underlying molecular biology of the tumor. OBJECTIVE: The aim of this work is to provide an overview of the molecular biological characteristics of the genetics, epigenetics, and immunology of OPSCC. MATERIALS AND METHODS: A literature review was performed on a selection of genetic, epigenetic, and immunological factors characterizing OPSCC. RESULTS: The understanding of genetic aberrations and their consequences for cancerogenesis and tumor biology is increasing. Epigenetic phenomena are complementing functional relationships. However, epigenetic mechanisms of gene regulation are complex and much research is still required in this field. Immunological aspects of cancer molecular biology have moved into the focus in light of recent advances in the field of immunotherapy. CONCLUSION: The tumor biology of OPSCC is primarily defined by its HPV status. Additionally, HPV-independent genetic, epigenetic, and immunological signatures are being defined. From these advances, rationales for new treatment concepts may evolve.

[Tumor microenvironment in salivary gland carcinomas: Consequences for new therapeutic concepts]. / Das Tumormikromilieu bei Speicheldrüsenkarzinomen ­ mögliche Konsequenzen für neue Therapiekonzepte.

INTRODUCTION: Salivary gland carcinomas (SGCs) are rare tumors which represent a challenge for diagnosis and therapy due to their histological diversity and the different disease courses depending on the respective subtype. Little is known about the composition of the tumor microenvironment in SGCs. A more comprehensive understanding of the relevant molecular changes and immunological processes of the tumor and surrounding stroma could help to improve therapeutic efficiency, for example by adjuvant immunomodulation. METHODS: This manuscript highlights recent studies analyzing the composition of the tumor microenvironment in salivary gland carcinomas. RESULTS: The tumor microenvironment displays a significant diversity in the composition of immune cells among different tumor entities. In one third of the SGCs, an expression of cell surface molecule LAG3 on tumor infiltrating lymphocytes could be observed. LAG3-similar to CTLA­4 and PD-1-inhibits cellular proliferation, activation, and homeostasis of antitumor-effective T cells. Especially, prognostically less favorable entities such as salivary duct carcinomas and adenocarcinomas NOS (not otherwise specified) yielded higher expressions. CONCLUSIONS: LAG3 is particularly detectable in aggressive entities and advanced tumors. Hence, LAG3 inhibition poses a potential targeted therapy for advanced and metastatic SGCs.

Age-related changes in T lymphocytes of patients with head and neck squamous cell carcinoma.

INTRODUCTION: The number of aging cancer patients has increased continuously and will do so further in the future. The immune system of elderly people experiences critical changes over the time. Therefore, tumor-induced changes in the immune system are believed to differ in young and elderly cancer patients as well. METHODS: The effect of aging on the immune system was measured in peripheral blood lymphocytes (PBL) of healthy volunteers (n = 48, 21-84 yrs.) divided into three different age groups. Seventy years was set as a cut-off for defining subjects as elderly. Results were compared to two groups of adult cancer patients, which donated PBL and tumor infiltrating lymphocytes (TIL): young cancer patients (40-69 yrs.; blood: n = 13; TIL: n = 17) and elderly cancer patients (70-90 yrs.; blood: n = 20; TIL: n = 15) with head and neck squamous cell carcinoma (HNSCC). Frequencies and phenotypes of CD4+ and CD8+ T cells as well as regulatory T cells (Treg) were assessed by flow cytometry. RESULTS: We observed lower frequencies of CD8+ cytotoxic T cells during aging in both groups. Frequencies of tumor infiltrating regulatory T cells were significantly higher than in the peripheral blood but showed a significant decline in older tumor patients. With increasing age, expression of immunosuppressive CD73 and CCR7 was lower and expression of PD1 elevated on peripheral T cells in healthy volunteers and tumor patients. CONCLUSION: Immunosenescence takes place in healthy donors and cancer patients. Our results suggest that in elderly tumor patients, the immune system is impaired and the tumor-induced immune escape is less pronounced. The increased expression of PD1 implies the potential for effective immunotherapies in elderly, as treatment with checkpoint inhibitors could be more beneficial for elderly HNSCC patients.

[Oncoimmunology in old age]. / Onkoimmunologie im Alter.

Physiological aging processes of the immune system are associated with an increased susceptibility to infectious, autoimmune and tumor diseases. In accordance with the general demographic development the number of tumor patients in advanced age also increases. An end to this development is not yet foreseeable. In tumor treatment, immunotherapy with checkpoint inhibitors is becoming increasingly more important; however, only a few studies on the efficacy and side-effect profiles in older patients exist so far. In this review article the changes in the immune system in old age and the influence on carcinogenesis are discussed. In addition, the current state of research on the immunotherapy of patients in advanced age who suffer from head and neck cancer is presented.

[Salivary gland malignancies-highlights of the 2019 ASCO Annual Meeting]. / Maligne Speicheldrüsentumoren ­ Highlights der ASCO-Jahrestagung 2019.

BACKGROUND: Due to their comparatively low incidence, salivary gland carcinomas have only been the subject of isolated clinical studies in recent years. In addition, surgery with/without adjuvant radiotherapy is considered standard treatment. Systemic therapies have received little attention and are only used for advanced and distantly metastasized salivary gland malignancies. OBJECTIVE: The contributions with the highest relevance for this year's meeting of the American Society of Clinical Oncology (ASCO) were to be reviewed. MATERIALS AND METHODS: A total of 12 contributions pertaining to clinical studies on salivary gland malignancies were identified, eight of which were classified as relevant for future changes to the therapeutic landscape. RESULTS: Three studies dealt with different combinations of a checkpoint blockade, and each showed a low response rate. In addition, studies on targeted therapies depending on the results of a mutation analysis and expression of HER2 or the androgen receptor were presented. CONCLUSION: A favorable response of HER2-positive salivary gland carcinomas to an antibody-drug conjugate could be shown. Furthermore, no convincing data regarding response to programmed cell death protein 1 (PD1)/programmed death ligand 1 (PD-L1) inhibitors in advanced salivary gland cancer were presented. Further studies and ideas for new treatment approaches will be needed to improve the therapeutic options for patients with salivary gland carcinoma.

[Immunotherapy for head and neck cancer : Highlights of the 2019 ASCO Annual Meeting]. / Immuntherapie von Kopf-Hals-Tumoren : Highlights der ASCO-Jahrestagung 2019.

BACKGROUND: In the field of immunotherapy of head and neck squamous cell carcinoma (HNSCC), a high level of study activity can still be observed. The results of the Keynote-048 study on first-line therapy with pembrolizumab were a highlight at this year's meeting of the American Society of Clinical Oncology (ASCO). MATERIALS AND METHODS: All abstracts and presentations on immunotherapy of head and neck tumors presented at ASCO 2019 were evaluated for relevance and the most interesting studies were summarized. RESULTS: The Keynote-048 study showed an improvement in overall survival with pembrolizumab monotherapy for patients with measurable programmed cell death ligand 1 (PD-L1) expression according to the combined positive score (CPS), and for the whole cohort with the combination of pembrolizumab and platin/5-fluorouracil (FU). The EAGLE study on durvalumab ± tremelimumab in second-line therapy did not demonstrate any improvement in response rates or overall survival compared to standard therapy. In addition, several new immunotherapeutic approaches and combinations were presented. CONCLUSION: The results of the Keynote-048 study have already led to the approval of pembrolizumab in the first line for platin-sensitive HNSCC in the USA and the expected approval in Europe will presumably change the therapeutic landscape in the long term. In the future, effective therapies for patients without a response to programmed cell death 1 (PD-1)/PD-L1 inhibition will be needed.

[Subcutaneous foreign body granuloma after neck dissection and adjuvant radiation]. / Subkutane "Perlschnur" nach Neck-Dissection unter adjuvanter Radiatio.

This article presents an oncologic patient with oropharyngeal cancer. After surgery with bilateral neck dissection and adjuvant radiation, the patient developed foreign body granuloma in the area of neck dissection in addition to cervical and mediastinal granuloma. Possible differential diagnoses in this situation are sarcoidosis or tumor-derived sarcoid-like lesions, but also metastases. Therefore, intensified follow-up is particularly important for oncologic patients developing granulomas.

[Immunotherapy highlights of the ASCO annual meeting 2018 for head and neck cancers]. / Highlights der ASCO Jahrestagung 2018 zur Immuntherapie von Kopf-Hals-Tumoren.

BACKGROUND: Immunotherapeutic strategies are becoming increasingly more important for head and neck cancer and numerous clinical trials were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) 2018. OBJECTIVE: In this review the most interesting clinical trials and trial results for immunotherapy of head and neck cancer are summarized. MATERIAL AND METHODS: All abstracts and presentations on immunotherapy of head and neck cancer at the annual meeting of the ASCO 2018 were screened to select the most interesting trials for a more detailed analysis. RESULTS: For head and neck cancer, practice changing phase III trial results were missing, but several noteworthy new strategies and trial results for immunotherapy were presented. Neoadjuvant immunotherapy trials, results concerning immunotherapy in old age, prognostic implications of immune-mediated adverse events and new immunotherapy combinations are summarized in this article. CONCLUSION: The role of immunotherapy for the treatment of head and neck cancer is markedly increasing. Many pioneering trials are currently ongoing, in the phase of data analysis or in planning.

Polyfunctionality of CD4+ T lymphocytes is increased after chemoradiotherapy of head and neck squamous cell carcinoma.

BACKGROUND: For head and neck squamous cell cancer (HNSCC), standard therapy consists of surgery, radiation, and/or chemotherapy. Antineoplastic immunotherapy could be an option in an adjuvant setting and is already in palliation. A functional immune system is a prerequisite for successful immunotherapy. However, effects of the standard-of-care therapy on the patients' immune system are not fully understood. METHODS: Peripheral blood mononuclear cells (PBMC) were collected from patients with HNSCC (n = 37) and healthy controls (n = 10). PBMC were stimulated with staphylococcal enterotoxin B (SEB). Simultaneous expression of various cytokines was measured in CD4+ and CD8+ T cells by multicolor flow cytometry, and polyfunctional cytokine expression profiles were determined on a single-cell basis. RESULTS: Expression levels of all measured cytokines in CD4+ T cells were higher in patients after chemoradiotherapy (CRT) as compared to untreated HNSCC patients or normal controls. After CRT, the frequency of polyfunctional CD4+ T cells, which simultaneously expressed multiple cytokines, was significantly increased as compared to untreated patients (p < 0.01). CONCLUSION: CRT increases polyfunctionality of CD4+ T cells in HNSCC patients, suggesting that standard-of-care therapy can promote immune activity in immune cells. These polyfunctional CD4+ T cells in the blood of treated HNSCC patients are expected to be responsive to subsequent immunotherapeutic approaches.

[Immuno-, radio-, and chemotherapeutic studies in head and neck cancer : Highlights of the ASCO Annual Meeting 2017]. / Immun-, radio- und chemotherapeutische Studien bei Kopf-Hals-Tumoren : Highlights der ASCO-Jahrestagung 2017.

In recent years, immunotherapy has been shown to be a promising approach for the treatment of various tumor entities. Due to further pharmacological developments and new studies, the checkpoint inhibitors have now arrived in the clinic. To date, patients with cancers in the head and neck region have benefited from these agents as part of a palliative therapy. Current clinical trials are testing other indications for the checkpoint inhibitors as monotherapy or in combination with other therapeutic approaches. The following article summarizes the highlights of the American Society of Clinical Oncology (ASCO) Annual Meeting.

[The 8th edition of the AJCC Cancer Staging Manual : Updates in otorhinolaryngology, head and neck surgery]. / Die 8. Ausgabe der TNM­Klassifikation : Neuerungen für das Fachgebiet Hals­Nasen­Ohren­Heilkunde, Kopf- und Halschirurgie.

BACKGROUND: The TNM system is an established tool for classification of solid tumors by means of tumor size and extent, the involvement of local lymph nodes, and the presence of distant metastases. The classification was established in order to visualize prognostic implications and to allow establishment of systematic therapeutic algorithms. Since the beginning of 2017 a revised version of the classification has applied. Particularly the classification of otorhinolaryngologic tumors has been thoroughly revised in the 8th edition, partly on the basis of new prognostically relevant parameters, such as infection with oncogenic human papillomavirus (HPV) subtypes. MATERIALS AND METHODS: The 8th edition of the American Joint Committee on Cancer (AJCC) served as a basis for the review. The highlighted changes were supplemented by a literature review and the most important elements were summarized. RESULTS: Substantial changes were made for oropharyngeal carcinomas caused by HPV, for the classification of lymph node metastases under consideration of extranodal extension, and for classification of tumors of the oral cavity. Due to their frequency and special biology, skin tumors in the head and neck area are now described in a separate chapter. CONCLUSION: The new classification is a challenge for all specialties involved in tumor staging and therapy. The advantage for the patient lies in a more accurately adjustable treatment modality through more precise classification of tumors. Good collaboration and rapid implementation of the new classification is required in all disciplines involved in head neck tumor diagnostics and therapy.

Application of a computer-assisted flexible endoscope system for transoral surgery of the hypopharynx and upper esophagus.

Zenker's diverticulum is a common pathology in the transition zone of the posterior hypopharynx and esophagus. Surgical treatment is routinely performed by ENT and general surgeons. Besides the traditional open transcervical diverticulectomy, the introduction of transoral rigid treatment led to a paradigm change and is now the preferred treatment option for patients who are fit for general anesthesia. The implementation of interventional flexible endoscopy has opened another new micro-invasive approach for patients with high morbidity. Here, we present the potential utilization of a flexible, single port, robot-assisted, and physician-controlled endoscope system to facilitate transoral surgical access to the hypopharynx and upper esophagus. Transoral surgery of the hypopharynx and upper esophagus was performed in human cadavers (n = 5) using the Flex System (Medrobotics, Raynham, USA). Anatomical landmarks were identified, and posterior cricothyroid myotomy was performed with compatible flexible instruments in all cases. The approach to the hypopharynx and upper esophagus using the Flex system is feasible in a cadaveric model. Myotomy with a flexible tool and needle knife (from the perspective of treatment of Zenker´s diverticulum) was successful in all cases. Visualization of the surgical site with the system's HD camera is suitable and the flexible instruments meet the special needs of a micro-invasive transoral approach. Zenker´s diverticulum can be potentially treated with a transoral minimally invasive approach using a computer-assisted flexible endoscope system. This setup could be of advantage in patients with reduced mobility of the cervical spine to prevent open transcervical surgery. In our study, the Flex system enabled advanced visualization of the surgical site and extended intervention options, compared to standard flexible endoscopic treatment. However, general anesthesia is mandatory for the presented approach. Application in live patients with actual pathologies of the hypopharynx and upper esophagus will have to prove suitability for the treatment of Zenker's diverticulum. Further development of the system could include improved instrumentation and an adoption by other disciplines with challenging anatomy such as colorectal surgery.

[Immunomodulation as innovative therapy for head and neck tumors : Current developments]. / Immunmodulation als innovative Therapie bei Kopf-Hals-Tumoren : Aktuelle Entwicklungen.

Head and neck squamous cell carcinoma (HNSCC) is characterized by its intense immune suppression and its elaborate immune escape mechanisms. Due to the fact that survival rates remain low, the role of immunotherapy has become more important and the focus of current clinical studies has shifted toward antibody-based immune checkpoint modulation. Application of immunotherapy in curative settings or for prevention of recurrent disease would be desirable.

[Immunotherapy of head and neck tumors: Highlights of the ASCO Meeting 2015]. / Immuntherapie von Kopf-Hals-Karzinomen: Highlights des ASCO-Kongresses 2015.

BACKGROUND: In recent years, new immunotherapeutic drugs have become available: the so-called immune checkpoint modulators. With these drugs, unprecedented treatment results have been achieved in different malignant diseases; primarily malignant melanoma, but also in various other malignomas. These achievements have revolutionized the oncologic treatment landscape. This quickly expanding research field, driven by revolutionary treatment results, has put immunotherapy in the focus of attention. OBJECTIVE: Due to rapid developments in the field of immunotherapy, this article aims at introducing, illustrating, and summarizing the field of modern immunotherapy, based on recently presented clinical data from the Annual Meeting of the American Society of Clinical Oncology (ASCO) 2015. MATERIALS AND METHODS: The most important ASCO Meeting 2015 immunotherapy trials for head and neck squamous cell carcinoma (HNSCC) were identified, summarized, and discussed with respect to the current state of research. RESULTS: The oncologic landscape of clinical trials is currently dominated by the new immune checkpoint modulating drugs. Also for HNSCC, a variety of clinical trials and substances are under way. The current primary focus of these trials is targeting and inhibiting the programmed death 1 (PD-1) axis. Cancer immunotherapy with immune checkpoint modulating drugs seems to be independent of human papilloma virus (HPV) status. Robust predictive markers for patient selection are not yet available. CONCLUSION: Current data from clinical trials with immune checkpoint modulators are promising. In the coming years, integration of these drugs into clinical routine can be expected. With regard to the public health economic burden and potential adverse events, the identification of predictive markers for patient selection is a major task for future trials.