Abstract
Background
A predominant side effect of radiotherapy for head and neck cancer is salivary gland hypofunction and xerostomia leading to debilitating oral disorders and impaired quality of ...life (QoL). Intraglandular mesenchymal stem cell therapy has shown promising results as a treatment for xerostomia.
Methods
This is a randomised, double-blinded, placebo-controlled, parallel-group, prospective, single-centre trial investigating the safety, tolerability, and effectiveness of allogeneic stem cells as a treatment for radiation-induced hyposalivation and xerostomia for previous head and neck cancer patients.
We will include a total of 120 patients who previously have been treated with radiotherapy for a head and neck cancer in Denmark. Participants will be randomly assigned using block randomisation to one of two parallel groups in a 1:1 ratio to receive ultrasound-guided injection of allogeneic adipose-derived mesenchymal stem cell (ASC) (
n
= 60) or placebo (
n
= 60) into the submandibular glands. Placebo will consist of CryoStor10 (BiolifeSolutions), the freeze media for ASCs containing 10% dimethyl sulfoxide (DMSO). The primary endpoint is change in unstimulated whole saliva flow rate. The secondary endpoints are change in stimulated whole saliva flow rate, QoL, and composition of saliva. Further secondary endpoints are safety and immune response (human leukocyte antigen (HLA) response) to the stem cells will be assessed. Patients are evaluated at baseline (before treatment), after 4 months, and after 12 months. All study personnel, except study personnel thawing and preparing the treatment for injection, and participants will be blinded to group assignment. Unblinded study personnel will not participate in the outcome assessment.
Discussion
The trials will investigate the efficacy and safety of ASC injection to the submandibular gland as a potential new treatment for post-radiation xerostomia. We hope the results will pave the way for a clinically relevant treatment to ameliorate patients with xerostomia, a severely hampering condition.
Trial registration
The study is approved by the Danish Data Protection Agency (protocol number P-2020-1164), the National Ethics Committee protocol number: (Protocol number: 1802872), and the Danish Medical Agency (2018-000348-24). The protocol was registered at the ClinicalTrials.gov database (NCT04776538).
Dual-energy computed tomography (DECT) is an emerging technology in radiotherapy (RT). Here, we investigate split-filter DECT throughout the RT treatment chain as compared to single-energy CT (SECT).
...DECT scans were acquired with a tin-gold split-filter at 140 kV resulting in a low- and high-energy CT reconstruction (recon). Ten cancer patients (four head-and-neck (HN), three rectum, two anal/pelvisand one abdomen) were DECT scanned without and with iodine administered. A cylindrical and an anthropomorphic HN phantom were scanned with DECT and 120 kV SECT. The DECT images generated were: 120 kV SECT-equivalent (CTmix), virtual monoenergetic images (VMIs), iodine map, virtual non-contrast (VNC), effective atomic number (Zeff), and relative electron density (ρe,w). The clinical utility of these recons was investigated for calibration, delineation, dose calculation and image-guided RT (IGRT).
A calibration curve for 75 keV VMI had a root-mean-square-error (RMSE) of 34 HU in closest agreement with the RSME of SECT calibration. This correlated with a phantom-based dosimetric agreement to SECT of γ1%1mm > 98%. A 40 keV VMI recon was most promising to improve tumor delineation accuracy with an average evaluation score of 1.6 corresponding to “partial improvement”. The dosimetric impact of iodine was in general < 2%. For this setup, VNC vs. non-contrast CTmix based dose calculations are considered equivalent. SECT- and DECT-based IGRT was in agreement within the setup uncertainty.
DECT-based RT could be a feasible alternative to SECT providing additional recons to support the different steps of the RT workflow.
To study the associations between development of moderate to severe skin rash, clinical outcome, and single nucleotide polymorphisms (SNPs) in candidate genes in head and neck cancer patients from ...the DAHANCA 19 trial receiving the EGFR-inhibitor zalutumumab concurrently with radiation treatment.
310 patients were included from the zalutumumab-arm of the DAHANCA 19 study. Nine SNPs in the candidate genes EGFR, EGF, AREG, FCGR2A, FCGR3A, and CCND1 were successfully determined in 294 patients. Clinical endpoints were moderate to severe skin rash within the first 3 weeks of treatment, loco-regional failure (LRF), disease-specific survival (DSS), and overall survival (OS).
During the first 3 weeks of treatment, 86% of the patients experienced any grade of rash and 17% experienced a moderate to severe rash. Development of moderate to severe rash was not associated with LRF or DSS but was associated with improved OS, HR 0.40 (95% CI: 0.19-0.82). The effect was similar for patients with p16-negative or p16-positive tumors (p = .90). After adjustment for comorbidity and performance status, the minor alleles of SNPs rs9996584 and rs13104811 located near the AREG gene were significantly associated with increased risk of moderate to severe rash with per-allele odds ratios of 1.61 (1.01-2.54) and 1.56 (1.00-2.44). SNP rs11942466 located close to rs9996584 had a borderline significant association, and none of the other SNPS were significantly associated with risk of skin rash.
Moderate to severe skin rash after zalutumumab during radiation treatment was associated with improved OS, independent of HPV/p16-status. Genetic variants in AREG (member of the EGF family) may be associated with increased risk of skin rash.
•The majority (80 %) of loco-regional failures in HNSCC arise within high-dose volume.•Treatment failure in HNSCC is in most cases due to tumor radioresistance.•Most failure sites in both ...p16-positive and negative SCC were high-dose failures.
Patients with failure after primary radiotherapy (RT) for head and neck squamous cell carcinoma (HNSCC) have a poor prognosis. This study investigates pattern of failure after primary curatively intended IMRT in a randomized controlled trial in relation to HPV/p16 status.
Patients with HNSCC of the oral cavity, oropharynx (OPSCC), hypopharynx or larynx were treated with primary curative IMRT (+/-cisplatin) and concomitant nimorazole between 2007 and 12. Of 608 patients, 151 had loco-regional failure within five years, from whom 130 pairs of scans (planning-CT and diagnostic failure scan) were collected and deformably co-registered. Point of origin-based pattern of failure analysis was conducted, including distance to CTV1 and GTV, and estimated dose coverage of the point of origin.
Of 130 patients with pairs of scans, 104 (80 %) had at least one local or regional failure site covered by 95 % of prescribed dose and 87 (67 %) of the failures had point of origin within the high-dose CTV (CTV1). Of failures from primary p16 + OPSCC, the majority of both mucosal (84 %) and nodal (61 %) failures were covered by curative doses. For p16− tumors (oral cavity, OPSCC p16neg, hypopharynx and larynx), 75 % of mucosal and 66 % of nodal failures were high-dose failures.
Radioresistance is the primary cause of failure after RT for HNSCC irrespective of HPV/p16 status. Thus, focus on predictors for the response to RT is warranted to identify patients with higher risk of high-dose failure that might benefit from intensified treatment regimens.
•Head and neck magnetic resonance imaging and computed tomography co-registration.•Validation of planning and recurrence scan co-registration separated in time.•Mean distances to agreement for ...regions of interest/normal tissue were tolerable.
MRI (magnetic resonance imaging) scans are frequently used in follow-up after radiotherapy for head and neck cancer. With the overall aim of enabling MRI-based pattern of failure analysis, this study evaluated the accuracy of recurrence MRI (rMRI) deformable co-registration with planning CT (computed tomography)-scans (pCT). Uncertainty of anatomical changes between pCT and rMRI was assessed by similarity metric analyses of co-registered image structures from 19 patients. Average mean distance to agreement and Dice similarity coefficient performed adequately. Our findings provide proof of concept for reliable co-registration of pCT and rMRI months to years apart for MRI-based pattern of failure analysis.
•Early mortality after radical RT/CRT in HNSCC patients is often not cancer-related.•An early non-cancer risk prediction model was developed.•After internal validation, the AUC was 0.74 and ...calibration was good.•Pneumonia was estimated to be the cause of death in 32% of early non-cancer deaths.•The provided risk estimates can help select patients for supportive interventions.
In patients with head and neck squamous cell carcinoma (HNSCC), curative-intent radiotherapy (RT) and chemoradiotherapy (CRT) are associated with substantial acute morbidity and 5–10% of patients die within 180 days of treatment initiation. Most of these early deaths occur without HNSCC recurrence or progression and may therefore be preventable to some extent. We developed a prediction tool to estimate the risk of non-HNSCC mortality occurring within the first 180 days followingRT/CRT initiation.
Patients with HNSCC treated with RT/CRT, including postoperative RT/CRT, at Rigshospitalet or Herlev Hospitals between 2010–2017 were identified in the Danish Head and Neck Cancer Group (DAHANCA) database. Predictor variables included age, stage, performance status, tumor subsite including p16 status, comorbidity, postoperative status, smoking and pre-treatment albumin levels. The 180-day non-HNSCCmortality risk was estimated by combining cause-specific Cox regression models.
We included 2209 patients. The 180-day non-HNSCCmortality rate was 4.4% and almostone third (31.6%) of non-HNSCCdeathswere caused by pneumonia.After internal model validation, the area under the receiver operating curve was 0.74 (95% CI: 0.66–0.81) and calibration was good for risk predictions ranging from 0% to 20%.
We developed a prediction tool to estimate the 180-day non-HNSCC mortality risk. This tool can be used to select high-risk patients for supportive interventions aiming to improve survival rates, and is availablefor interactive use at https://emriskpred.shinyapps.io/EMNED_App/.
•Visualising 3D mean standard deviation in contouring emphasizes areas of OARs with the highest interoberver disagreements.•Areas with high interobserver variation should be further discussed to ...clarify clinical guidelines.•Even between experts, there is some remaining variation which could serve as comparator for automated delineation tools.
•Tumor volume, SLC3A2 and CD44 are prognostic for high-dose failure in HNSCC.•SLC3A2 is a biomarker for high-dose failure in (C-)RT for p16 + oropharyngeal SCC.•Tumor volume is the main driver for ...high-dose failure in p16- HNSCC.•Tumor hypoxia was not prognostic in patients treated with concomitant nimorazole.
Reliable and accessible biomarkers for patients with Head and Neck Squamous Cell Carcinoma (HNSCC) are warranted for biologically driven radiotherapy (RT). This study aimed to investigate the prognostic value of putative cancer stem cell (CSC) markers, hypoxia, and tumor volume using loco-regional high-dose failure (HDF) as endpoint.
Tumor tissue was retrieved from patients treated with primary chemo-(C-)RT and nimorazole for HNSCC in the Danish Head and Neck Cancer Study Group (DAHANCA) 19 study. Tumor volume, hypoxic classification, and expression of CSC markers CD44, SLC3A2, and MET were analyzed. For patients with eligible data on all parameters (n = 340), the risk of HDF following primary chemo-(C-)RT were analyzed by these biomarkers as a whole and stratified for p16-positive oropharynx (p16 + OPSCC) vs p16-negative (p16-) tumors (oral cavity, p16- oropharynx, hypopharynx and larynx).
Higher risk of HDF was seen for patients with larger primary and nodal volume (>25 cm3, Hazard Ratio (HR): 3.00 95 % CI: 1.73–5.18), high SLC3A2 (HR: 2.99 1.28–6.99), CD44 (>30 % positive, HR: 2.29 1.05–5.00), and p16- tumors (HR: 2.53 1.05–6.11). p16- tumors had a higher CSC marker expression than p16 + OPSCC. The factors associated with the highest risk of HDF were larger volume (HR: 3.29 1.79–6.04) for p16- tumors (n = 178) and high SLC3A2 (HR: 6.19 1.58–24.23) for p16 + OPSCC (n = 162).
Tumor volume, p16, and CSC markers are potential biomarkers for HDF for patients with HNSCC treated with (C-)RT. Lower expression of CSC in p16 + OPSCC may contribute to better tumor control.
No effective treatment exists for radiation-induced xerostomia. The objective of this study was to compare the effect of adipose-derived mesenchymal stem/stromal cell (ASC) injection, relative to ...placebo, on salivary gland function in patients with radiation-induced xerostomia.
In this single-centre, double-blind, placebo-controlled trial, patients with hyposalivation were randomised to receive ultrasound-guided injections of allogeneic ASCs or placebo into the submandibular glands. Patients were followed for 4 months. We evaluated unstimulated whole salivary flow rate (UWS), stimulated salivary flow rate, and patient-reported outcomes. Adverse events were recorded and immune response determined in blood samples.
We enrolled 120 patients. ASC treatment resulted in a statistically significant UWS increase of 0.04 95% confidence interval (CI), 0.02-0.06 mL/min (38%) compared with pretreatment baseline whereas placebo treatment did not cause a significant increase 0.01 (95% CI, -0.01 to 0.04) mL/min (21%). Both the ASC and placebo treatment yielded notable symptom reductions, with dry mouth decreasing by 13.6 and 7.7 units, sticky saliva decreased by 14.8 and 9.3 units, swallowing difficulties decreased by 7.9 and 8.0 units, and the summary score of the Xerostomia Questionnaire decreased 5.9 and 5.1 units for the ASC and placebo arms, respectively. We found no statistically significant group difference between the ASC and placebo arms for any of the outcomes.
We could not confirm superiority of the ASC relative to placebo. ASC therapy significantly improved UWS in previous patients with head and neck cancer, whereas placebo resulted in an insignificant increase.
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