Association of histological features with laryngeal squamous cell carcinoma recurrences:a population-based study of 1502 patients in the Netherlands

BACKGROUND: Recurrences remain an important problem in laryngeal squamous cell carcinoma. Little has been described about histological characteristics of the primary laryngeal tumor that may be associated with recurrences. Identifying risk factors for recurrences might help in adapting treatment or follow-up. Using real-life population-based data, we aimed to identify histological features of the primary tumor associated with recurrences and overall survival. MATERIAL AND METHODS: Demographic, clinical and treatment information on all first primary invasive laryngeal tumors diagnosed in 2010–2014 (N = 3705) were extracted from the population-based nationwide Netherlands cancer registry (NCR) and linked to PALGA, the nationwide Dutch pathology registry, to obtain data on histological factors and recurrences. For a random 1502 patients histological information i.e., keratinization, perineural invasion (PNI+), vascular invasion (VI+), growth pattern, degree of differentiation, extracapsular spread (ECS+), cartilage- and bone invasion and extralaryngeal extension, was manually extracted from narrative pathology reports and analyzed for locoregional recurrence and overall survival using cox regression analysis. RESULTS: In total, 299 patients developed a locoregional recurrence and 555 patients died. Keratinization (HR = 0.96 (95%CI: 0.68–1.34) p = 0.79), two or three adverse characteristics (PNI+, VI+, non-cohesive growth) (HR = 1.38 (95% CI: 0.63–3.01) p = 0.42), and ECS+ (HR = 1.38 (95% CI: 0.48–4.02) p = 0.55) were not associated to recurrence. For death, also no significant association was found. CONCLUSION: In this population-based real-life dataset on laryngeal carcinoma in the Netherlands, histological factors were not associated with locoregional recurrences or overall survival, but future studies should investigate the role of these features in treatment decisions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-09533-0

Effectiveness of a guided self-help exercise program tailored to patients treated with total laryngectomy:Results of a multi-center randomized controlled trial

Objective: To investigate the effectiveness of a guided self-help exercise program on swallowing, speech, and shoulder problems in patients treated with total laryngectomy (TL). Materials and methods: This randomized controlled trial included patients treated with TL in the last 5 years. Patients were randomized into the intervention group (self-help exercise program with flexibility, range-of-motion and lymphedema exercises and self-care education program) or control group (self-care education program). Both groups completed measurements before and 3 and 6-months after randomization. The primary outcome was swallowing problems (SWAL-QOL). Secondary outcomes were speech problems (SHI), shoulder problems (SDQ), self-management (patient activation: PAM) and health-related quality of life (HRQOL: EORTC QLQ-C30/H&N35). Adherence was defined as moderate-high in case a patient exercised >1 per day. Linear mixed model analyses were conducted to investigate the effectiveness of the intervention and to investigate whether neck dissection, treatment indication (primary/salvage TL), time since treatment, severity of problems, and preferred format (online/booklet) moderated the effectiveness. Results: Moderate-high adherence to the exercise program was 59%. The intervention group (n = 46) reported less swallowing and communication problems over time compared to the control group (n = 46) (p-value = 0.013 and 0.004). No difference was found on speech, shoulder problems, patient activation and HRQOL. Time since treatment moderated the effectiveness on speech problems (p-value = 0.025): patients within 6 months after surgery benefitted most from the intervention. Being treated with a neck dissection, treatment indication, severity of problems and format did not moderate the effectiveness. Conclusion: The guided self-help exercise program improves swallowing and communication. Trial registration. NTR5255

National Protocol for Model-Based Selection for Proton Therapy in Head and Neck Cancer

In the Netherlands, the model-based approach is used to identify patients with head and neck cancer who may benefit most from proton therapy in terms of prevention of late radiation-induced side effects in comparison with photon therapy. To this purpose, a National Indication Protocol Proton therapy for Head and Neck Cancer patients (NIPP-HNC) was developed, which has been approved by the health care authorities. When patients qualify according to the guidelines of the NIPP-HNC, proton therapy is fully reimbursed. This article describes the procedures that were followed to develop this NIPP-HNC and provides all necessary information to introduce model-based selection for patients with head and neck cancer into routine clinical practice.</p

Patterns of long-term swallowing dysfunction after definitive radiotherapy or chemoradiation

Objectives: To identify patterns of long-term, radiation-induced swallowing dysfunction after definitive radiotherapy with or without chemotherapy (RT or CHRT) and to determine which factors may explain these patterns over time.Material and methods: The study population consisted of 238 consecutive head and neck cancer patients treated with RT or CHRT. The primary endpoint was &gt;= grade 2 swallowing dysfunction at 6, 12, 18 and 24 months after treatment. Cluster analysis was used to identify different patterns over time. The differences between the mean dose to the swallowing organs at risk for each pattern were determined by using dose maps.Results: The cluster analysis revealed five patterns of swallowing dysfunction: low persistent, intermediate persistent, severe persistent, transient and progressive. Patients with high dose to the upper pharyngeal, laryngeal and lower pharyngeal region had the highest risk of severe persistent swallowing dysfunction. Transient problems mainly occurred after high dose to the laryngeal and lower pharyngeal regions, combined with moderate dose to the upper pharyngeal region. The progressive pattern was mainly seen after moderate dose to the upper pharyngeal region.Conclusions: Various patterns of swallowing dysfunction after definitive RT or CHRT can be identified over time. This could reflect different underlying biological processes. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.</p

Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification

Background: Organoids are in vitro three-dimensional structures that can be grown from patient tissue. Head and neck cancer (HNC) is a collective term used for multiple tumor types including squamous cell carcinomas and salivary gland adenocarcinomas.Methods: Organoids were established from HNC patient tumor tissue and characterized using immunohistochemistry and DNA sequencing. Organoids were exposed to chemo- and radiotherapy and a panel of targeted agents. Organoid response was correlated with patient clinical response. CRISPR-Cas9-based gene editing of organoids was applied for biomarker validation.Findings: A HNC biobank consisting of 110 models, including 65 tumor models, was generated. Organoids retained DNA alterations found in HNC. Comparison of organoid and patient response to radiotherapy (primary [n = 6] and adjuvant [n = 15]) indicated potential for guiding treatment options in the adjuvant setting. In organoids, the radio-sensitizing potential of cisplatin and carboplatin could be validated. However, cetuximab conveyed radioprotection in most models. HNC-targeted treatments were tested on 31 models, indicating possible novel treatment options with the potential for treatment stratification in the future. Activating PIK3CA mutations did not predict alpelisib response in organoids. Protein arginine methyltransferase 5 (PRMT5) inhibitors were identified as a potential treatment option for cyclin-dependent kinase inhibitor 2A (CDKN2A) null HNC.Conclusions: Organoids hold potential as a diagnostic tool in personalized medicine for HNC. In vitro organoid response to radiotherapy (RT) showed a trend that mimics clinical response, indicating the predictive potential of patient-derived organoids. Moreover, organoids could be used for biomarker discovery and validation.</p

Development and validation of a prediction model for tube feeding dependence after curative (chemo-) radiation in head and neck cancer

BACKGROUND: Curative radiotherapy or chemoradiation for head and neck cancer (HNC) may result in severe acute and late side effects, including tube feeding dependence. The purpose of this prospective cohort study was to develop a prediction model for tube feeding dependence 6 months (TUBEM6) after curative (chemo-) radiotherapy in HNC patients. PATIENTS AND METHODS: Tube feeding dependence was scored prospectively. To develop the multivariable model, a group LASSO analysis was carried out, with TUBEM6 as the primary endpoint (n = 427). The model was then validated in a test cohort (n = 183). The training cohort was divided into three groups based on the risk of TUBEM6 to test whether the model could be extrapolated to later time points (12, 18 and 24 months). RESULTS: Most important predictors for TUBEM6 were weight loss prior to treatment, advanced T-stage, positive N-stage, bilateral neck irradiation, accelerated radiotherapy and chemoradiation. Model performance was good, with an Area under the Curve of 0.86 in the training cohort and 0.82 in the test cohort. The TUBEM6-based risk groups were significantly associated with tube feeding dependence at later time points (p<0.001). CONCLUSION: We established an externally validated predictive model for tube feeding dependence after curative radiotherapy or chemoradiation, which can be used to predict TUBEM6

Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification

Background: Organoids are in vitro three-dimensional structures that can be grown from patient tissue. Head and neck cancer (HNC) is a collective term used for multiple tumor types including squamous cell carcinomas and salivary gland adenocarcinomas. Methods: Organoids were established from HNC patient tumor tissue and characterized using immunohistochemistry and DNA sequencing. Organoids were exposed to chemo- and radiotherapy and a panel of targeted agents. Organoid response was correlated with patient clinical response. CRISPR-Cas9-based gene editing of organoids was applied for biomarker validation. Findings: A HNC biobank consisting of 110 models, including 65 tumor models, was generated. Organoids retained DNA alterations found in HNC. Comparison of organoid and patient response to radiotherapy (primary [n = 6] and adjuvant [n = 15]) indicated potential for guiding treatment options in the adjuvant setting. In organoids, the radio-sensitizing potential of cisplatin and carboplatin could be validated. However, cetuximab conveyed radioprotection in most models. HNC-targeted treatments were tested on 31 models, indicating possible novel treatment options with the potential for treatment stratification in the future. Activating PIK3CA mutations did not predict alpelisib response in organoids. Protein arginine methyltransferase 5 (PRMT5) inhibitors were identified as a potential treatment option for cyclin-dependent kinase inhibitor 2A (CDKN2A) null HNC. Conclusions: Organoids hold potential as a diagnostic tool in personalized medicine for HNC. In vitro organoid response to radiotherapy (RT) showed a trend that mimics clinical response, indicating the predictive potential of patient-derived organoids. Moreover, organoids could be used for biomarker discovery and validation

Treatment of T3 laryngeal cancer in the Netherlands : A national survey

Background: Treatment strategies for T3 laryngeal carcinoma include radiotherapy (RT) with or without chemotherapy (CT) and sometimes surgery. We conducted a national survey to determine how T3 laryngeal carcinoma is currently being managed in the Netherlands.  Methods: A questionnaire on general treatment policy, also inquiring details on RT and CT, was sent to all 13 radiotherapy departments accredited for treatment of head and neck cancer (HNC) in the Netherlands.  Results: Twelve centers completed the questionnaire. All centers reported using RT with or without CT. Upfront laryngectomy is rarely performed. At 9/12 centers, CT is added to RT in cases with large tumors in T3N0 disease. Three centers use a volume criterion (3-6 cc); 6 centers don't specify "large" with such criteria. CT consists of cisplatin 3-weekly (7 centers) or weekly (2 centers), unless contra-indicated or age; 6 centers use an age limit of 70 years. RT is given concomitantly with CT 5×/week except at the 2 centers where cisplatin weekly is combined with 6 fractions/week. In case of RT only, treatment is accelerated. Lymph node levels II-IV are treated electively. In T3N+ disease, 11/12 centers treat non-bulky T3N1 with RT only. Volume criteria for combined CT-RT are the same as above. Two centers perform an upfront neck dissection in case of (resectable) N3 disease; 10 centers treat T3N2-3 cancer with primary CT-RT, 2 centers don't use the N-stage criterion. Total RT dose is 68-70 Gy, the elective dose varies between 46 and 57.75 Gy. Eight centers use a simultaneous integrated boost technique. Conclusions: Treatment of T3 laryngeal cancer in the Netherlands is generally comparable, with CT-RT for voluminous T3N0 and most T3N+ tumors, but there are some differences between the centers in the use of chemotherapy and the dose-fractionation schemes. Therefore, the aim of the National Platform RT HNC is further standardization of RT dose, fractionation and delivery techniques