Disease outcome and associated factors after definitive platinum based chemoradiotherapy for advanced stage HPV-negative head and neck cancer.

BACKGROUND: Definitive concomitant cisplatin-based chemoradiotherapy (CRT) is the current gold standard for most patients with advanced stage head and neck squamous cell carcinoma (HNSCC) of the pharynx and larynx. Since previous meta-analysis on CRT outcomes in HNSCC have been reported, advances have been made in radiotherapy techniques and clinical management, while HPV-status has been identified as a strong confounding prognostic factor in oropharyngeal cancer. Here, we present real-world outcome data from a large multicenter cohort of HPV-negative advanced stage HNSCC treated with CRT using contemporary IMRT-based techniques. METHOD: Retrospective data were collected from a multicenter cohort of 513 patients treated with definitive concurrent platinum-based CRT with curative intent between January 2009 and August 2017. Only patients with HPV-negative advanced stage (III-IV) HNSCC were included. A prognostic model for outcome was developed based on clinical parameters and compared to TNM. RESULTS: Nearly half of the 513 patients (49%) had an oropharyngeal tumor, often locally advanced (73.3% T3-T4b) and with involvement of the regional lymph nodes (84%). Most patients (84%) received cisplatin as single agent. In total 66% received the planned number of cycles and 75% reached a cumulative cisplatin dose of ≥200 mg/m2. Locoregional control was achieved in 324 (63%) patients during follow-up, and no association with tumor sites was observed (p = 0.48). Overall survival at 5 year follow-up was 47%, with a better survival for laryngeal cancer (p = 0.02) compared to other sites. A model with clinical variables (gender, high pre-treatment weight loss, N2c/N3-stage and <200 mg/m2 dose of cisplatin) provided a noticeably stronger association with overall survival than TNM-staging (C- index 0.68 vs 0.55). Simultaneous Integrated Boosting (SIB) significantly outperformed Sequential Boosting (SEQ) to reduce the development of distant metastasis (SEQ vs SIB: OR 1.91 (1.11-3.26; p = 0.02). CONCLUSION: Despite advances in clinical management, more than a third of patients with HPV-negative HNSCC do not complete CRT treatment protocols due to cisplatin toxicity. A model that consists of clinical variables and treatment parameters including cisplatin dose provided the strongest association with overall survival. Since cisplatin toxicity is a major obstacle in completing definitive CRT, the development of alternative and less toxic radiosensitizers is therefore warranted to improve treatment results. The association of RT-boost technique with distant metastasis is an important finding and requires further study.

Assessing the prognostic value of tumor-infiltrating CD57+ cells in advanced stage head and neck cancer using QuPath digital image analysis.

This study aimed to assess the prognostic value of intratumoral CD57+ cells in head and neck squamous cell carcinoma (HNSCC) and to examine the reproducibility of these analyses using QuPath. Pretreatment biopsies of 159 patients with HPV-negative, stage III/IV HNSCC treated with chemoradiotherapy were immunohistochemically stained for CD57. The number of CD57+ cells per mm2 tumor epithelium was quantified by two independent observers and by QuPath, software for digital pathology image analysis. Concordance between the observers and QuPath was assessed by intraclass correlation coefficients (ICC). The correlation between CD57 and clinicopathological characteristics was assessed; associations with clinical outcome were estimated using Cox proportional hazard analysis and visualized using Kaplan-Meier curves. The patient cohort had a 3-year OS of 65.8% with a median follow-up of 54 months. The number of CD57+ cells/mm2 tumor tissue did not correlate to OS, DFS, or LRC. N stage predicted prognosis (OS: HR 0.43, p = 0.008; DFS: HR 0.41, p = 0.003; LRC: HR 0.24, p = 0.007), as did WHO performance state (OS: HR 0.48, p = 0.028; LRC: 0.33, p = 0.039). Quantification by QuPath showed moderate to good concordance with two human observers (ICCs 0.836, CI 0.805-0.863, and 0.741, CI 0.692-0.783, respectively). In conclusion, the presence of CD57+ TILs did not correlate to prognosis in advanced stage, HPV-negative HNSCC patients treated with chemoradiotherapy. Substantial concordance between human observers and QuPath was found, confirming a promising future role for digital, algorithm driven image analysis.

Radiotherapy as nose preservation treatment strategy for cancer of the nasal vestibule: The Dutch experience.

BACKGROUND AND PURPOSE: Primary radiotherapy is often preferred for early-stage cancer of the nasal vestibule (CNV), combining high disease control with preservation of nasal anatomy. However, due to practice variation and an absence of comparative trials, no consensus exists on preference for brachytherapy (BT) or external beam radiotherapy (EBRT). We compared these modalities in terms of disease control, nose preservation rates and toxicity. MATERIALS AND METHODS: Medical records of 225 patients with T1-T2 squamous cell carcinoma of the nasal vestibule treated with 3D image-guided primary radiotherapy between Jan 2010 and Dec 2016 in 6 Dutch institutions were reviewed retrospectively. RESULTS: 153 of 225 patients were treated with BT, 65 with EBRT and 7 with other modalities. Median follow-up was 46 months. Overall 3-year local control (LC) and regional control (RC) were 87% and 89%. Five-year disease-specific survival (DSS) and overall survival (OS) were 94% and 82%. Three-year survival with preserved nose (SPN) was 76%. BT provided higher 3-year LC (95% vs 71%, p < 0.01) and SPN compared with EBRT (82% vs 61%, p < 0.01). Multivariable and propensity-score-matched cohort analyses confirmed better outcomes after BT. No difference was seen in DSS or OS. Five-year incidence of CTCAE 5.0 grade ≥2 toxicity was higher after BT (20% vs 3%, p = 0.03) and consisted mostly of radiation ulcers. 50% of all late toxicity recovered. CONCLUSION: In this largest-to-date multicenter analysis of T1-T2 CNV, BT achieved superior LC and SPN compared with EBRT. Grade 1-2 radiation ulcers occurred more frequently after brachytherapy, but were transient in half the cases. Considering these results, BT can be recommended as first-line treatment for T1-T2 CNV.

A Prospectively Validated Prognostic Model for Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck Based on Radiomics of Computed Tomography Images.

BACKGROUND: Locoregionally advanced head and neck squamous cell carcinoma (HNSCC) patients have high relapse and mortality rates. Imaging-based decision support may improve outcomes by optimising personalised treatment, and support patient risk stratification. We propose a multifactorial prognostic model including radiomics features to improve risk stratification for advanced HNSCC, compared to TNM eighth edition, the gold standard. PATIENT AND METHODS: Data of 666 retrospective- and 143 prospective-stage III-IVA/B HNSCC patients were collected. A multivariable Cox proportional-hazards model was trained to predict overall survival (OS) using diagnostic CT-based radiomics features extracted from the primary tumour. Separate analyses were performed using TNM8, tumour volume, clinical and biological variables, and combinations thereof with radiomics features. Patient risk stratification in three groups was assessed through Kaplan-Meier (KM) curves. A log-rank test was performed for significance (p-value < 0.05). The prognostic accuracy was reported through the concordance index (CI). RESULTS: A model combining an 11-feature radiomics signature, clinical and biological variables, TNM8, and volume could significantly stratify the validation cohort into three risk groups (p < 0∙01, CI of 0.79 as validation). CONCLUSION: A combination of radiomics features with other predictors can predict OS very accurately for advanced HNSCC patients and improves on the current gold standard of TNM8.

Development of a multiomics database for personalized prognostic forecasting in head and neck cancer: The Big Data to Decide EU Project.

BACKGROUND: Despite advances in treatments, 30% to 50% of stage III-IV head and neck squamous cell carcinoma (HNSCC) patients relapse within 2 years after treatment. The Big Data to Decide (BD2Decide) project aimed to build a database for prognostic prediction modeling. METHODS: Stage III-IV HNSCC patients with locoregionally advanced HNSCC treated with curative intent (1537) were included. Whole transcriptomics and radiomics analyses were performed using pretreatment tumor samples and computed tomography/magnetic resonance imaging scans, respectively. RESULTS: The entire cohort was composed of 71% male (1097)and 29% female (440): oral cavity (429, 28%), oropharynx (624, 41%), larynx (314, 20%), and hypopharynx (170, 11%); median follow-up 50.5 months. Transcriptomics and imaging data were available for 1284 (83%) and 1239 (80%) cases, respectively; 1047 (68%) patients shared both. CONCLUSIONS: This annotated database represents the HNSCC largest available repository and will enable to develop/validate a decision support system integrating multiscale data to explore through classical and machine learning models their prognostic role.

[18F]-HX4 PET/CT hypoxia in patients with squamous cell carcinoma of the head and neck treated with chemoradiotherapy: Prognostic results from two prospective trials.

INTRODUCTION: The presence of hypoxia in head-and-neck squamous cell carcinoma is a negative prognostic factor. PET imaging with [18F] HX4 can be used to visualize hypoxia, but it is currently unknown how this correlates with prognosis. We investigated the prognostic value of [18F] HX4 PET imaging in patients treated with definitive radio(chemo)therapy (RTx). MATERIALS AND METHODS: We analyzed 34 patients included in two prospective clinical trials (NCT01347281, NCT01504815). Static [18F] HX4 PET-CT images were collected, both pre-treatment (median 4 days before start RTx, range 1-16), as well as during RTx (median 13 days after start RTx, range 3-17 days). Static uptake at both time points (n = 33 pretreatment, n = 28 during RTx) and measured changes in hypoxic fraction (HF) and hypoxic volume (HV) (n = 27 with 2 time points) were analyzed. Univariate cox analyses were done for local progression free survival (PFS) and overall survival (OS) at both timepoints. Change in uptake was analyzed by comparing outcome with Kaplan-Meier curves and log-rank test between patients with increased and decreased/stable hypoxia, similarly between patients with and without residual hypoxia (rHV = ratio week 2/baseline HV with cutoff 0.2). Voxelwise Spearman correlation coefficients were calculated between normalized [18F] HX4 PET uptake at baseline and week 2. RESULTS: Analyses of static images showed no prognostic value for [18F] HX4 uptake. Analysis of dynamic changes showed that both OS and local PFS were significantly shorter (log-rank P < 0.05) in patients with an increase in HV during RTx and OS was significantly shorter in patients with rHV, with no correlation to HPV-status. The voxel-based correlation to evaluate spatial distribution yielded a median Spearman correlation coefficient of 0.45 (range 0.11-0.65). CONCLUSION: The change of [18F] HX4 uptake measured on [18F] HX4 PET early during treatment can be considered for implementation in predictive models. With these models patients with a worse prognosis can be selected for treatment intensification.

Privacy-preserving distributed learning of radiomics to predict overall survival and HPV status in head and neck cancer.

A major challenge in radiomics is assembling data from multiple centers. Sharing data between hospitals is restricted by legal and ethical regulations. Distributed learning is a technique, enabling training models on multicenter data without data leaving the hospitals ("privacy-preserving" distributed learning). This study tested feasibility of distributed learning of radiomics data for prediction of two year overall survival and HPV status in head and neck cancer (HNC) patients. Pretreatment CT images were collected from 1174 HNC patients in 6 different cohorts. 981 radiomic features were extracted using Z-Rad software implementation. Hierarchical clustering was performed to preselect features. Classification was done using logistic regression. In the validation dataset, the receiver operating characteristics (ROC) were compared between the models trained in the centralized and distributed manner. No difference in ROC was observed with respect to feature selection. The logistic regression coefficients were identical between the methods (absolute difference <10-7). In comparison of the full workflow (feature selection and classification), no significant difference in ROC was found between centralized and distributed models for both studied endpoints (DeLong p > 0.05). In conclusion, both feature selection and classification are feasible in a distributed manner using radiomics data, which opens new possibility for training more reliable radiomics models.

Disease-induced and treatment-induced alterations in body composition in locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Chemoradiation or bioradiation treatment (CRT/BRT) of locally advanced head and neck squamous cell carcinoma (LAHNSCC) comes with high toxicity rates, often leading to temporary tube feeding (TF) dependency. Cachexia is a common problem in LAHNSCC. Yet changes in body composition and muscle weakness during CRT/BRT are underexplored. Strong evidence on the effect of TF on body composition during treatment is lacking. The aim of this cohort study was to assess (i) the relationship of fat-free mass index (FFMI) and handgrip strength (HGS) with CRT/BRT toxicity and outcome, (ii) body composition in patients treated with chemoradiation (cisplatin) vs. bioradiation (cetuximab), and (iii) the effect of the current TF regime on body composition and muscle strength. METHODS: Locally advanced head and neck squamous cell carcinoma patients treated with CRT/BRT between January 2013 and December 2016 were included (n = 137). Baseline measurements of body composition (bioelectrical impedance analysis) and HGS were performed. Toxicity grades (Common Terminology Criteria for Adverse Events) were scored. In a subset of 69 patients, weight loss, body composition, and HGS were additionally assessed during and after CRT/BRT. TF was initiated according to the Dutch guidelines for malnutrition. RESULTS: In this cohort (68% male, mean age 59 ± 8 years), the incidence of baseline muscle wasting, defined as FFMI < P10 , was 29%. Muscle wasting was present in 23 of 100 (23%) chemoradiation patients and 17 of 37 (46%) bioradiation patients (P = 0.009). Muscle-wasted patients required more unplanned hospitalizations during CRT (P = 0.035). In the chemoradiation subset, dose-limiting toxicity was significantly higher in wasted vs. non-wasted patients (57% vs. 25%, P = 0.004). Median follow-up was 32 months. Multivariate Cox regression analysis identified muscle wasting as independent unfavourable prognostic factor for overall survival [hazard ratio 2.1 (95% CI 1.1-4.1), P = 0.022] and cisplatin as favourable prognostic factor [hazard ratio 0.3 (95% CI 0.2-0.6), P = 0.001]. Weight and HGS significantly decreased during CRT/BRT, -3.7 ± 3.5 kg (P < 0.001) and -3.1 ± 6.0 kg (P < 0.001), respectively. Sixty-four per cent of the patients required TF 21 days (range 0-59) after CRT/BRT initiation. Total weight loss during CRT/BRT was significantly (P = 0.007) higher in the total oral diet group (5.5 ± 3.7 kg) compared with the TF group (3.0 ± 3.2 kg). Loss of FFM and HGS was similar in both groups. CONCLUSIONS: In LAHNSCC patients undergoing CRT/BRT, FFMI < P10 is an unfavourable prognostic factor for overall survival, treatment toxicity, and tolerance. Patients experience significant weight and FFM loss during treatment. Current TF regime attenuates weight loss but does not overcome loss of muscle mass and function during therapy. Future interventions should consider nutritional intake and additional strategies specifically targeting metabolism, loss of muscle mass, and function.