Individual elective lymph node irradiation for the reduction of complications in head and neck cancer patients (iNode): A phase-I feasibility trial protocol

Introduction: The long-term complication rate in head-and-neck squamous cell carcinoma (HNSCC) patients caused by radiotherapy (RT) can be decreased by restricting elective neck irradiation (ENI) from large adjacent lymph node levels to only individual elective lymph nodes. The primary objective of this study is to treat the first HNSCC patients with individual elective lymph node irradiation by means of a Magnetic Resonance-linac (MR-linac) in order to assess the feasibility. Methods and analysis: In this phase I feasibility study, 20 patients will be included with histologically proven cT2-4N0-1M0 HNSCC originating from the oropharynx, hypopharynx or larynx, planned for treatment with primary radiotherapy and bilateral elective neck irradiation (ENI). Patients will be treated with 35 fractions in six weeks, according to the DAHANCA schedule. Individual lymph nodes inside the conventional lymph node levels will be categorized in low-risk, intermediate-risk and high-risk based on cytology, histology and imaging parameters. Low-risk and intermediate-risk lymph nodes will irradiated in 20 and 23 fractions respectively, with a fraction dose of 2 Gy (=40/46 Gy EQD2). The high-risk lymph nodes and the primary tumor will be irradiated in 35 fractions of 2 Gy (=70 Gy equivalent dose in 2 Gy fractions (EQD2)). To limit treatment burden, 20 fractions will be applied on the MR-linac. The last 15 fractions (sequential boost at the primary tumor, intermediate-risk and high-risk lymph nodes) will be applied on a conventional linear accelerator. The main study endpoint is the percentage of fractions that are successfully completed on the MR-linac. Ethics and dissemination: With individual elective lymph node irradiation we expect less toxicity and a better quality of life for HNSCC patients. However, as the treatment time on the MR-linac will be longer (30–45 vs 15 min per fraction) we need to examine if patients can endure this new treatment concept

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

Oncological outcome of vocal cord-only radiotherapy for cT1-T2 glottic laryngeal squamous cell carcinoma

Purpose: Early-stage glottic cancer can be treated with radiotherapy only. Modern radiotherapy solutions allow for individualized dose distributions, hypofractionation and sparing of organs at risk. The target volume used to be the entire voice box. This series describe the oncological outcome and toxicity of individualized vocal cord-only hypofractionated radiotherapy for early stage (cT1a-T2 N0). Methods: Retrospective cohort study with patients treated in a single center between 2014 and 2020. Results: A total of 93 patients were included. Local control rate was 100% for cT1a, 97% for cT1b and 77% for cT2. Risk factor for local recurrence was smoking during radiotherapy. Laryngectomy-free survival was 90% at 5 years. Grade III or higher late toxicity was 3.7%. Conclusion: Vocal cord-only hypofractionated radiotherapy appears to be oncologically safe in early-stage glottic cancer. Modern, image-guided radiotherapy led to comparable results as historical series with very limited late toxicity

Detectability and intra-fraction motion of individual elective lymph nodes in head and neck cancer patients on the Magnetic Resonance Image guided linear accelerator

Background and purpose: Individual elective lymph node irradiation instead of elective neck irradiation is a new concept for head-and-neck cancer (HNC) patients developed for the Magnetic Resonance Image guided linear accelerator (MR-linac). To prepare this, the detectability, volume changes and intra-fraction motion of elective lymph nodes on the MR-linac was assessed. Materials and methods: A total of 15 HNC patients underwent diagnostic pre-treatment MRI. Additionally, two MR-linac scans were obtained with a 10-minute time difference in the first week of radiation treatment. Elective lymph node contours inside lymph node levels (Ib-V) were segmented on the pre-treatment MRI and the MR-linac scans and compared on number and maximal transversal diameter. Intra-fraction motion of elective lymph nodes on the MR-linac was estimated using Center of Mass (COM) distances and incremental isotropic expansion of lymph node segmentations. Results: Of all 679 detected lymph nodes on the pre-treatment MRI, eight lymph nodes were not detectable on the first MR-linac scan and 16 new lymph nodes were detected. Lymph node diameters between the pre-treatment MRI scan and the MR-linac scan varied from −0.19 to + 0.13 mm. COM distances varied from 1.2 to 1.7 mm and lymph node contours had to be expanded with 3 mm. Conclusions: Nearly all elective lymph nodes were detectable on the 1.5T MR-linac scan with no major changes in target volumes compared to the pre-treatment MRI. Simulated intra-fraction motion during the MR-linac scans was smaller than the 5-mm margin that will be used in the first elective lymph node radiation treatment

Magnetic resonance guided elective neck irradiation targeting individual lymph nodes: A new concept

Background and purpose: Conventional elective neck irradiation (ENI) in head and neck cancer consists of radiotherapy (RT) to the regional lymph node (LN) levels contoured on computed tomography. Hybrid Magnetic Resonance (MR) - RT modalities, such as combined magnetic resonance imaging - linear accelerators (MRLs), might enable new ENI strategies in which individual non-suspect lymph nodes (i-LNs) are targeted. In this treatment planning study, new MR-based strategies targeting i-LNs (i-ENI) were compared to conventional treatment. Materials and methods: All i-LNs were delineated on MR images of ten retrospectively selected patients with T2-4aN0M0 laryngeal cancer. Three strategies were considered. Strategy A: Conventional ENI delivered with a conventional linear accelerator (35x 1.55 Gy). Strategy B: MRL-based i-ENI (35x 1.55 Gy) to the individual lymph nodes including a background dose to the conventional elective neck volumes (35x 1.03 Gy). Strategy C: Same as Strategy B, but without background dose. In all plans the dose prescription to the primary tumor was 35x 2 Gy. Mean dose (Dmean) reductions in the organs at risk (OAR) were compared using the Wilcoxon signed rank test. Results: Compared to conventional ENI (strategy A), significant Dmean reductions of 6.0 Gy and 8.0 Gy were observed in the submandibular glands, of 9.4 Gy and 13 Gy in the carotid arteries and of 9.9 Gy and 19.4 Gy in the thyroid for strategy B and C, respectively. Large inter-patient variations of Dmean reductions were observed in all OARs. Conclusion: MRL-based i-ENI is a new promising concept that could reduce the mean dose to OARs in the neck significantly for patients with laryngeal cancer

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