Publications by authors named "C Rene Leemans"

457 Publications

The unveiled reality of human papillomavirus as risk factor for oral cavity squamous cell carcinoma.

Int J Cancer 2021 Feb 26. Epub 2021 Feb 26.

Amsterdam UMC, Vrije Universiteit Amsterdam, Otolaryngology/Head and Neck Surgery, Cancer Center Amsterdam, Amsterdam, Netherlands.

The prognostic impact of human papillomavirus (HPV) in oropharyngeal cancer is generally acknowledged, and HPV-status is assessed routinely in clinical practice. Paradoxically, while the oral cavity seems the predilection site for productive HPV-infections, figures on HPV-attribution in oral cavity squamous cell carcinoma (OCSCC) differ widely, and prognostic impact is uncertain. Major obstacles are the lack of reproducible assays for non-oropharyngeal cancers, the relatively small cohorts studied, and consequently the shortfall of convincing data. In this study, we used a validated, nucleic acid-based workflow to assess HPV-prevalence in a consecutive cohort of 1,016 OCSCCs, and investigated its prognostic impact. In parallel, we analyzed p16-immunohistochemistry (p16-IHC) as surrogate marker for transforming HPV-infection and independent prognosticator. All OCSCC-patients diagnosed between 2008-2014 at two Dutch university medical centers were included (N=1,069). Formalin-fixed, paraffin-embedded (FFPE)-samples of 1,016 OCSCCs could be retrieved. Punch biopsies were taken from the tumor area in the FFPE-blocks and tested for HPV. P16-IHC was performed on 580 OCSCCs, including all HPV-positive tumors. From 940 samples (92.5%) nucleic acids were of sufficient quality for HPV-testing. In total 21 (2.2%) OCSCCs were HPV DNA-positive. All HPV DNA-positive tumors were E6 mRNA-positive and considered as true HPV-positive. There was no difference in survival between HPV-positive and HPV-negative OCSCCs. In total 46 of 580 (7.9%) OCSCCs were p16-immunopositive, including all HPV-positive tumors. Survival was similar in p16-positive and p16-negative OCSCCs. To conclude, HPV-prevalence is very low in OCSCC and neither HPV-status nor p16-status affects outcome. Based on these data, determining HPV-status in OCSCC seems irrelevant.
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http://dx.doi.org/10.1002/ijc.33514DOI Listing
February 2021

Neuroendocrine neoplasms of the middle ear: Unpredictable tumor behavior and tendency for recurrence.

Head Neck 2021 Feb 19. Epub 2021 Feb 19.

Department of Otolaryngology - Head and Neck Surgery, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: Middle ear adenomatous neuroendocrine tumors (MEANTs) are rare temporal bone tumors. This study evaluates its clinical behavior and therapy outcome.

Method: Retrospective case review in a tertiary referral center evaluating histopathology, immunohistochemistry, treatment, and outcome.

Results: Nine patients were diagnosed with MEANT. One patient presented with locally invasive tumor and underwent extensive en-bloc tumor resection with adjuvant radiotherapy. Seven of eight patients with locally non-aggressive tumor confined to the tympanomastoid space underwent tumor resection. Two patients were disease-free, five presented recurrence, even after apparent successful surgery. All tumors showed neuroendocrine features. Histopathology and immunohistochemistry did not yield prognostic tumor characteristics.

Conclusion: MEANTs are rare tumors with uncertain biological behavior and subsequent unpredictable clinical course. The preferred treatment is complete surgical tumor resection. They have a high tendency for recurrence, irrespective of negative intermediary surgery. As of yet, there are no prognostic biomarkers, including histopathology and immunohistochemistry.
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http://dx.doi.org/10.1002/hed.26658DOI Listing
February 2021

Sleep quality trajectories from head and neck cancer diagnosis to six months after treatment.

Oral Oncol 2021 Feb 12;115:105211. Epub 2021 Feb 12.

Department of Clinical, Neuro- and Developmental Psychology, Faculty of Behavioral and Movement Sciences & Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands; Cancer Center Amsterdam Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Otolaryngology - Head and Neck Surgery, Amsterdam, the Netherlands. Electronic address:

Objectives: Patients with head and neck cancer (HNC) often report disturbances in their sleep quality, impairing their quality of life. This study aims to examine the trajectories of sleep quality from diagnosis up to 6-month after treatment, as well as the pre-treatment risk factors for poor sleep trajectories.

Materials And Methods: Sleep quality (Pittsburgh sleep quality index) was measured shortly after diagnosis (pre-treatment), and at 3 and 6 months after finishing treatment. Patients were categorized into 5 trajectory groups. We examined the association of sleep quality trajectories with sociodemographic and clinical characteristics, coping style, HNC symptoms, and psychological distress.

Results: Among 412 included patients, about a half either had a persistent good sleep (37.6%) or an improving (16.5%) trajectory. About a third had a persistent poor sleep (21.8%) or worsening (10.9%) sleep trajectory. The remaining patients (13.1%), alternated between good and poor sleep. Using persistent good sleep as a reference outcome, persistent poor sleepers were more likely to be woman (odds ratio [OR] = 1.98, 95% confidence interval [CI] 1.01-3.90), use painkillers prior to treatment (OR = 2.52, 95% CI 1.33-4.77), and have more pre-treatment anxiety symptoms (OR = 1.26, 95% CI 1.15-1.38).

Conclusion: Unfavorable sleep quality trajectories are prevalent among HNC patients from pre-treatment to 6-month after treatment. A periodic sleep evaluation starting shortly after HNC diagnosis is necessary to identify persistent sleep problems, especially among high-risk group.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105211DOI Listing
February 2021

Effect of Stepped Care on Sexual Interest and Enjoyment in Distressed Patients with Head and Neck Cancer: A Randomized Controlled Trial.

Sex Med 2021 Feb 15;9(1):100304. Epub 2021 Jan 15.

Department of Sexology and Psychosomatic Gynaecology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:

Introduction: A recent randomized controlled trial (RCT) in patients with head and neck cancer (HNC) with psychological distress showed that a stepped care (SC) program targeting psychological distress compared with care as usual (CAU), is (cost)effective in reducing psychological distress.

Aim: The aim of the present study was to investigate whether SC can coalleviate problems with sexual interest and enjoyment. A secondary aim was to investigate whether the presence of an unmet sexual health need and having a psychiatric disorder (depression or anxiety) at baseline moderated any effect of SC on these sexual variables until 1-year follow-up.

Methods: HNC survivors (N = 134), randomized to SC or CAU, were assessed regarding their sexual interest and enjoyment before and after the intervention and at 3, 6, 9, and 12 months follow-up. Linear mixed models were used to evaluate differences in the course of sexual interest and enjoyment between SC and CAU.

Main Outcome Measure: The "sexuality" symptom subscale, part of the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Head and Neck Cancer-specific module.

Results: Of all patients, 76.1% had an unmet sexual need at baseline, 24.6% had a psychiatric disorder (anxiety or depression). SC did not reduce problems with sexual interest and enjoyment at any of the follow-up measurements compared with CAU (P = .85). This was neither moderated by an unmet sexual health need at baseline (P = .64) nor by the presence of a psychiatric disorder at baseline (P = .59).

Conclusion: A substantial number of patients with HNC have unmet sexual health needs. SC targeting psychological distress does not reduce problems with sexuality in these patients. Interventions specifically targeting sexuality are recommended. Schutte LER, Melissant HC, Jansen F, et al. Effect of Stepped Care on Sexual Interest and Enjoyment in Distressed Patients with Head and Neck Cancer: A Randomized Controlled Trial. Sex Med 2021;9:100304.
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http://dx.doi.org/10.1016/j.esxm.2020.100304DOI Listing
February 2021

The course of health-related quality of life from diagnosis to two years follow-up in patients with oropharyngeal cancer: does HPV status matter?

Support Care Cancer 2021 Jan 17. Epub 2021 Jan 17.

Department of Otolaryngology-Head and Neck Surgery, Amsterdam UMC, Vrije Universiteit Amsterdam, P.O. Box 7057, 1007, MB, Amsterdam, the Netherlands.

Purpose: To investigate the course of health-related quality of life (HRQOL) from diagnosis to 2 years follow-up among patients with oropharyngeal cancer (OPSCC), in relation to human papilloma virus (HPV) status.

Methods: This study included 270 OPSCC patients. Age, sex, tumor sublocation, tumor stage, HPV status, treatment modality, comorbidity, smoking, and alcohol use were retrieved from medical records. HPV status was positive when p16 and HPV DNA tests were both positive. HRQOL was assessed using the EORTC QLQ-C30/QLQ-H&N35 pretreatment and at 6 weeks, 6, 12, 18, and 24 months after treatment. To compare the course of HRQOL between patients with an HPV-positive versus HPV-negative tumor, linear and logistic mixed models were used.

Results: Patients with an HPV-positive tumor (29%) were more often male, diagnosed with a tumor of the tonsil or base of the tongue, treated with single treatment, had fewer comorbidities, were less often current smokers and had lower alcohol consumption. Adjusted for confounders, the course of global quality of life, physical, role, and social functioning, fatigue, pain, insomnia, and appetite loss was significantly different: patients with an HPV-positive tumor scored better before treatment, worsened during treatment, and recovered better and faster at follow-up, compared to patients with an HPV-negative tumor. The course of emotional functioning and oral pain was also significantly different between the two groups, but with other trajectories.

Conclusion: The course of HRQOL is different in patients with an HPV-positive tumor versus an HPV-negative tumor, adjusted for sociodemographic, clinical, and lifestyle confounders.
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http://dx.doi.org/10.1007/s00520-020-05932-wDOI Listing
January 2021

The eHealth self-management application 'Oncokompas' that supports cancer survivors to improve health-related quality of life and reduce symptoms: which groups benefit most?

Acta Oncol 2020 Dec 21:1-9. Epub 2020 Dec 21.

Department of Clinical, Neuro- and Developmental Psychology, Amsterdam Public Health research institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: Oncokompas is a web-based self-management application that supports cancer survivors to monitor their health-related quality of life (HRQOL) and symptoms, and to obtain personalised feedback and tailored options for supportive care. In a large randomised controlled trial among survivors of head and neck cancer, colorectal cancer, and breast cancer and (non-)Hodgkin lymphoma, Oncokompas proved to improve HRQOL, and to reduce several tumour-specific symptoms. Effect sizes were however small, and no effect was observed on the primary outcome patient activation. Therefore, this study aims to explore which subgroups of cancer survivors may especially benefit from Oncokompas.

Materials And Methods: Cancer survivors ( = 625) were randomly assigned to the intervention group (access to Oncokompas,  = 320) or control group (6 months waiting list,  = 305). Outcome measures were HRQOL, tumour-specific symptoms, and patient activation. Potential moderators included socio-demographic (sex, age, marital status, education, employment), clinical (tumour type, stage, time since diagnosis, treatment modality, comorbidities), and personal factors (self-efficacy, personal control, health literacy, Internet use), and patient activation, mental adjustment to cancer, HRQOL, symptoms, and need for supportive care, measured at baseline. Linear mixed models were performed to investigate potential moderators.

Results: The intervention effect on HRQOL was the largest among cancer survivors with low to moderate self-efficacy, and among those with high personal control and those with high health literacy scores. Cancer survivors with higher baseline symptom scores benefitted more on head and neck (pain in the mouth, social eating, swallowing, coughing, trismus), and colorectal cancer (weight) specific symptoms.

Discussion: Oncokompas seems most effective in reducing symptoms in head and neck cancer and colorectal cancer survivors who report a higher burden of tumour-specific symptoms. Oncokompas seems most effective in improving HRQOL in cancer survivors with lower self-efficacy, and in cancer survivors with higher personal control, and higher health literacy.
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http://dx.doi.org/10.1080/0284186X.2020.1851764DOI Listing
December 2020

European white paper: oropharyngeal dysphagia in head and neck cancer.

Eur Arch Otorhinolaryngol 2021 Feb 19;278(2):577-616. Epub 2020 Dec 19.

Gastrointestinal Physiology Laboratory, Hospital de Mataró, Universitat Autònoma de Barcelona, Mataró, Spain.

Purpose: To develop a European White Paper document on oropharyngeal dysphagia (OD) in head and neck cancer (HNC). There are wide variations in the management of OD associated with HNC across Europe.

Methods: Experts in the management of specific aspects of OD in HNC across Europe were delegated by their professional medical and multidisciplinary societies to contribute to this document. Evidence is based on systematic reviews, consensus-based position statements, and expert opinion.

Results: Twenty-four sections on HNC-specific OD topics.

Conclusion: This European White Paper summarizes current best practice on management of OD in HNC, providing recommendations to support patients and health professionals. The body of literature and its level of evidence on diagnostics and treatment for OD in HNC remain poor. This is in the context of an expected increase in the prevalence of OD due to HNC in the near future. Contributing factors to increased prevalence include aging of our European population (including HNC patients) and an increase in human papillomavirus (HPV) related cancer, despite the introduction of HPV vaccination in various countries. We recommend timely implementation of OD screening in HNC patients while emphasizing the need for robust scientific research on the treatment of OD in HNC. Meanwhile, its management remains a challenge for European professional associations and policymakers.
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http://dx.doi.org/10.1007/s00405-020-06507-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826315PMC
February 2021

Health-related quality of life and overall survival: a prospective study in patients with head and neck cancer treated with radiotherapy.

Qual Life Res 2020 Dec 8. Epub 2020 Dec 8.

Amsterdam University Medical Centers, Department of Otolaryngology-Head and Neck Surgery, Amsterdam, The Netherlands.

Purpose: We aimed to examine whether pre-treatment, post-treatment and change in health-related quality of Life (HRQoL) is associated with survival, in patients with head and neck cancer (HNC).

Methods: We included 948 newly diagnosed HNC patients treated with primary or adjuvant (chemo)radiotherapy with curative intent. The EORTC QLQ-C30 questionnaire was assessed pre-treatment and at 6 weeks, 6 months and 12 months post-treatment. Multivariable Cox regression analyses were performed to examine whether HRQoL at all time points and changes in HRQoL over time were associated with survival, after adjusting for demographic, clinical and lifestyle-related variables.

Results: Higher HRQoL scores were significantly associated with improved 5-year overall survival at all time points, except for the subscale global QoL at 6 weeks. Changes in HRQoL at 6 weeks post-treatment compared to pre-treatment were not significantly associated with survival. Changes in physical (HR: 0.88 95% CI: 0.82-0.96) and emotional functioning (HR: 0.90 95% CI: 0.85-0.96) from pre-treatment to 6 months post-treatment and changes in global QOL, and physical, emotional, and social functioning from pre-treatment to 12 months post-treatment were significantly associated with survival.

Conclusion: Higher HRQoL reported pre-treatment and post-treatment (6 weeks, 6 months and 12 months) are significantly associated with improved survival, as well as changes in HRQoL at 6 and 12 months compared to pre-treatment. Our results highlight the value of monitoring HRQoL and to identify those patients that report decreased or deteriorated HRQOL. This may help to further improve cancer care in a timely and efficient manner.
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http://dx.doi.org/10.1007/s11136-020-02716-xDOI Listing
December 2020

Head and neck squamous cell carcinoma.

Nat Rev Dis Primers 2020 11 26;6(1):92. Epub 2020 Nov 26.

Department of Otolaryngology-Head and Neck Surgery, University of California at San Francisco, San Francisco, CA, USA.

Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies.
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http://dx.doi.org/10.1038/s41572-020-00224-3DOI Listing
November 2020

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

Head Neck 2021 Feb 27;43(2):601-612. Epub 2020 Oct 27.

Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

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.
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http://dx.doi.org/10.1002/hed.26515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820974PMC
February 2021

The Additional Value of Ultrafast DCE-MRI to DWI-MRI and 18F-FDG-PET to Detect Occult Primary Head and Neck Squamous Cell Carcinoma.

Cancers (Basel) 2020 Sep 30;12(10). Epub 2020 Sep 30.

Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

To evaluate diagnostic accuracy of qualitative analysis and interobserver agreement of single ultrafast-DCE, DWI or F-FDG-PET and the combination of modalities for the detection of unknown primary tumor (UPT) in patients presenting with cervical lymph node metastasis from squamous cell carcinoma (SCC). Between 2014-2019, patients with histologically proven cervical lymph node metastasis of UPT SCC were prospectively included and underwent DWI, ultrafast-DCE, and F-FDG-PET/CT. Qualitative assessment was performed by two observers per modality. Interobserver agreement was calculated using the proportion specific agreement. Diagnostic accuracy of combined use of DWI, ultrafast-DCE and F-FDG-PET/CT was assessed. Twenty-nine patients were included (20 males. [68%], median age 60 years). Nine (31%) primary tumors remained occult. Ultrafast-DCE added reader confidence for suspicious locations (one additional true positive (5%), 2 decisive true malignant (10%). The per-location analysis showed highest specific positive agreement for ultrafast-DCE (77.6%). The per-location rating showed highest sensitivity (95%, 95%CI = 75.1-99.9, YI = 0.814) when either one of all modalities was scored positive, and 97.4% (95%CI = 93.5-99.3, YI = 0.774) specificity when co-detected on all. The per-patient analysis showed highest sensitivity (100%) for F-FDG-PET/CT (YI = 0.222) and either DWI or PET (YI = 0.111). Despite highest trends, no significant differences were found. The per-patient analysis showed highest specific positive agreement when co-detected on all modalities (55.6%, 95%CI = 21.2-86.3, YI = 0.456). Ultrafast-DCE showed potential to improve detection of unknown primary tumors in addition to DWI and F-FDG-PET/CT in patients with cervical squamous cell carcinoma lymph node metastasis. The combined use of ultrafast-DCE, DWI and F-FDG-PET/CT yielded highest sensitivity.
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http://dx.doi.org/10.3390/cancers12102826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600235PMC
September 2020

Predictive value of quantitative F-FDG-PET radiomics analysis in patients with head and neck squamous cell carcinoma.

EJNMMI Res 2020 Sep 7;10(1):102. Epub 2020 Sep 7.

Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center, De Boelelaan 1117, PO Box 7057, 1007, Amsterdam, MB, Netherlands.

Background: Radiomics is aimed at image-based tumor phenotyping, enabling application within clinical-decision-support-systems to improve diagnostic accuracy and allow for personalized treatment. The purpose was to identify predictive 18-fluor-fluoro-2-deoxyglucose (F-FDG) positron-emission tomography (PET) radiomic features to predict recurrence, distant metastasis, and overall survival in patients with head and neck squamous cell carcinoma treated with chemoradiotherapy.

Methods: Between 2012 and 2018, 103 retrospectively (training cohort) and 71 consecutively included patients (validation cohort) underwent F-FDG-PET/CT imaging. The 434 extracted radiomic features were subjected, after redundancy filtering, to a projection resulting in outcome-independent meta-features (factors). Correlations between clinical, first-order F-FDG-PET parameters (e.g., SUVmean), and factors were assessed. Factors were combined with F-FDG-PET and clinical parameters in a multivariable survival regression and validated. A clinically applicable risk-stratification was constructed for patients' outcome.

Results: Based on 124 retained radiomic features from 103 patients, 8 factors were constructed. Recurrence prediction was significantly most accurate by combining HPV-status, SUVmean, SUVpeak, factor 3 (histogram gradient and long-run-low-grey-level-emphasis), factor 4 (volume-difference, coarseness, and grey-level-non-uniformity), and factor 6 (histogram variation coefficient) (CI = 0.645). Distant metastasis prediction was most accurate assessing metabolic-active tumor volume (MATV)(CI = 0.627). Overall survival prediction was most accurate using HPV-status, SUVmean, SUVmax, factor 1 (least-axis-length, non-uniformity, high-dependence-of-high grey-levels), and factor 5 (aspherity, major-axis-length, inversed-compactness and, inversed-flatness) (CI = 0.764).

Conclusions: Combining HPV-status, first-order F-FDG-PET parameters, and complementary radiomic factors was most accurate for time-to-event prediction. Predictive phenotype-specific tumor characteristics and interactions might be captured and retained using radiomic factors, which allows for personalized risk stratification and optimizing personalized cancer care.

Trial Registration: Trial NL3946 (NTR4111), local ethics commission reference: Prediction 2013.191 and 2016.498. Registered 7 August 2013, https://www.trialregister.nl/trial/3946.
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http://dx.doi.org/10.1186/s13550-020-00686-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477048PMC
September 2020

Is the introduction of more advanced radiotherapy techniques for locally-advanced head and neck cancer associated with improved quality of life and reduced symptom burden?

Radiother Oncol 2020 Oct 3;151:298-303. Epub 2020 Sep 3.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Radiation Oncology, Cancer Center Amsterdam, Netherlands. Electronic address:

Technical improvements in head and neck cancer radiotherapy over the last decade have resulted in substantial reductions in dose to organs-at-risk. For a mix of tumors, we saw less xerostomia moving from 3D-conformal to more advanced techniques. For oropharynx-only there were additional improvements, including in global quality-of-life and sticky saliva.
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http://dx.doi.org/10.1016/j.radonc.2020.08.026DOI Listing
October 2020

Body image distress in head and neck cancer patients: what are we looking at?

Support Care Cancer 2021 Apr 3;29(4):2161-2169. Epub 2020 Sep 3.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Otolaryngology-Head and Neck Surgery, Amsterdam Public Health Research Institute, Cancer Center Amsterdam, P.O. Box 7057, 1007, Amsterdam, MB, Netherlands.

Purpose: The aim of the present study is to investigate the prevalence of body image distress among head and neck cancer (HNC) patients after treatment and to examine its association with sociodemographic and clinical factors, health-related quality of life (HRQOL), HNC symptoms, sexuality, self-compassion, and psychological distress. Second, we aim to explore daily life experiences of HNC patients regarding body image.

Methods: A cross-sectional survey among HNC patients investigated the prevalence of body image distress based on the Body Image Scale. Multivariable logistic regression analysis was applied to study associations with sociodemographic and clinical factors, HRQOL (EORTC QLQ-C30), HNC symptoms (QLQ-HN43), sexuality (FSFI-6; IIEF-5), self-compassion (SCS-SF), and psychological distress (HADS). Qualitative data from a body image writing intervention was used to explore experiences in daily life related to body image.

Results: Body image distress was prevalent in 13-20% (depending on cut-off scores) of 233 HNC patients. Symptoms of depression (p < 0.001), younger age (p < 0.001), problems with social contact (p = 0.001), problems with wound healing (p = 0.013), and larger extent of surgery (p = 0.014) were associated with having body image distress. This model explained 67% of variance. Writing interventions of 40 HNC patients showed that negative body image experiences were related to appearance and function, with social functioning problems described most often.

Conclusion: Prevalence of body image distress in HNC patients, using different cut-off scores, is 13-20%. Younger patients, patients after extensive surgery, and patients who had wound healing problems are most at risk. There is a significant association between body image distress and depressive symptoms and social functioning.
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http://dx.doi.org/10.1007/s00520-020-05725-1DOI Listing
April 2021

Multiparametric functional MRI and F-FDG-PET for survival prediction in patients with head and neck squamous cell carcinoma treated with (chemo)radiation.

Eur Radiol 2021 Feb 26;31(2):616-628. Epub 2020 Aug 26.

Department of Radiology and Nuclear Medicine, Amsterdam UMC, De Boelelaan 1117, Amsterdam, The Netherlands.

Objectives: To assess (I) correlations between diffusion-weighted (DWI), intravoxel incoherent motion (IVIM), dynamic contrast-enhanced (DCE) MRI, and F-FDG-PET/CT imaging parameters capturing tumor characteristics and (II) their predictive value of locoregional recurrence-free survival (LRFS) and overall survival (OS) in patients with head and neck squamous cell carcinoma (HNSCC) treated with (chemo)radiotherapy.

Methods: Between 2014 and 2018, patients with histopathologically proven HNSCC, planned for curative (chemo) radiotherapy, were prospectively included. Pretreatment clinical, anatomical, and functional imaging parameters (obtained by DWI/IVIM, DCE-MRI, and F-FDG-PET/CT) were extracted for primary tumors (PT) and lymph node metastases. Correlations and differences between parameters were assessed. The predictive value of LRFS and OS was assessed, performing univariable, multivariable Cox and CoxBoost regression analyses.

Results: In total, 70 patients were included. Significant correlations between F-FDG-PET parameters and DWI-/DCE volume parameters were found (r > 0.442, p < 0.002). The combination of HPV (HR = 0.903), intoxications (HR = 1.065), PT ADC (HR = 1.252), K (HR = 1.223), and V (HR = 1.215) was predictive for LRFS (C-index = 0.546; p = 0.023). N-stage (HR = 1.058), HPV positivity (HR = 0.886), hypopharyngeal tumor location (HR = 1.111), ADC (HR = 1.102), ADC (HR = 1.137), D* (HR = 0.862), K (HR = 1.106), V (HR = 1.195), SUV (HR = 1.094), and TLG (HR = 1.433) were predictive for OS (C-index = 0.664; p = 0.046).

Conclusions: Functional imaging parameters, performing DWI/IVIM, DCE-MRI, and F-FDG-PET/CT, yielded complementary value in capturing tumor characteristics. More specific, intoxications, HPV-negative status, large tumor volume-related parameters, high permeability (K), and high extravascular extracellular space (V) parameters were predictive for adverse locoregional recurrence-free survival and adverse overall survival. Low cellularity (high ADC) and high metabolism (high SUV) were additionally predictive for decreased overall survival. These different predictive factors added to estimated locoregional and overall survival.

Key Points: • Parameters of DWI/IVIM, DCE-MRI, and 18F-FDG-PET/CT were able to capture complementary tumor characteristics. • Multivariable analysis revealed that intoxications, HPV negativity, large tumor volume and high vascular permeability (K), and extravascular extracellular space (Ve) were complementary predictive for locoregional recurrence. • In addition to predictive parameters for locoregional recurrence, also high cellularity (low ADC) and high metabolism (high SUV) were complementary predictive for overall survival.
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http://dx.doi.org/10.1007/s00330-020-07163-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813703PMC
February 2021

Evaluation of the modified Pittsburgh classification for predicting the disease-free survival outcome of squamous cell carcinoma of the external auditory canal.

Head Neck 2020 Dec 13;42(12):3609-3622. Epub 2020 Aug 13.

Department of Otorhinolaryngology and Head and Neck Surgery, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is a rare disease, which is commonly classified with the modified Pittsburgh classification. Our aim was to evaluate the predictive performance of this classification in relation to disease-free survival (DFS).

Methods: We examined retrospective data from a nationwide Dutch cohort study including patients with primary EAC SCC. These data were combined with individual patient data from the literature. Using the combined data, the predictive performances were calculated using the c-index.

Results: A total of 381 patients were included, 294 for clinical and 281 for the pathological classification analyses. The c-indices of the clinical and the pathological modified Pittsburgh classification predicting DFS were 0.725 (0.668-0.782) and 0.729 (0.672-0.786), respectively.

Conclusion: The predictive performance of the modified Pittsburgh classification system as such appears to be acceptable to predict the DFS of EAC SCC. Other factors need to be added to a future model to improve the predicted performance.
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http://dx.doi.org/10.1002/hed.26424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754129PMC
December 2020

Salvage surgery in head and neck cancer.

Oral Dis 2021 Jan 21;27(1):117-124. Epub 2020 Sep 21.

Department of Otolaryngology- Head and Neck Surgery, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

Salvage surgery after failed organ preservation treatment offers challenges for both the patient and the surgeon. The outcome is often uncertain and even today, 5-year overall survival does not exceed 50 per cent. The chemoradiotherapy induced toxicity asks for meticulous discussion and planning in a multidisciplinary manner in a changing environment of increasing incidence of human papillomavirus induced oropharyngeal tumours, evolving surgical techniques and patient participation. Herein, we discuss the latest literature on salvage surgery and the need for identifying the proper prognosticators to ensure for an optimal treatment plan in potentially salvageable patients.
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http://dx.doi.org/10.1111/odi.13582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821237PMC
January 2021

Adherence to pretreatment and intratreatment imaging of head and neck squamous cell carcinoma patients undergoing (chemo) radiotherapy in a research setting.

Clin Imaging 2021 Jan 9;69:82-90. Epub 2020 Jul 9.

Department of Radiology and Nuclear Medicine, Amsterdam UMC, De Boelelaan 1117, Amsterdam, Netherlands.

Purpose: The emerge of improved personalized treatment adaptations and outcome prediction is accompanied with increasing non-invasive assessments in early treatment phase, leading to increased patient burden. This study assessed the adherence of patients with head and neck squamous cell carcinoma (HNSCC) to undergo pretreatment and research-related intratreatment imaging, and assessed which factors caused drop-out.

Method: Between 2013 and 2019, advanced-staged HNSCC patients were prospectively included, underwent (chemo) radiotherapy with curative intent and planned for both pre-treatment and intratreatment sequential 18F-FDG-PET/CT, 18F-FDG-PET/MRI and thereafter MRI (including DWI/DCE). Drop-out-factors were described as healthcare-related (logistics and imaging-system defects) and patient-related (psychological, physical, not-specified). Common Toxicity Criteria (CTC) were routinely scored by radiation/medical oncologists throughout the first 3 weeks, and compared between patient drop-outs and who complete imaging.

Results: Ninety-seven patients (mean age 61 ± 6.8 years) were included; 95 patients (97.9%) underwent pretreatment imaging and 63 (64.9%) intratreatment imaging. For 18F-FDG-PET/CT, 18F-FDG-PET/MRI and MRI pretreatment drop-outs were 2, 10 and 3 patients and for intratreatment drop-outs were 34, 39 and 35 patients, respectively. Patient-related drop-out-factors were physical (n = 16, e.g. dysphagia), psychological (n = 6, e.g. claustrophobia) and non-specified (n = 12). Healthcare-related drop-out-factors were logistics (n = 6) and 18F-FDG-PET/CT-/MRI-system defects (n = 2). The CTC mucosal toxicity was significantly higher (p = 0.023) at week 2 of (chemo)radiotherapy in patient drop-outs than with complete imaging.

Conclusions: The drop-out frequency of advanced-staged HNSCC patients for imaging during (chemo)radiotherapy in a research-setting was high and mainly patient-related. Treatment of patient-related inconveniences, communication of rationale and healthcare-related imaging protocol efficiency improvements may contribute to improved adherence.
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http://dx.doi.org/10.1016/j.clinimag.2020.06.047DOI Listing
January 2021

Cost-utility of an eHealth application 'Oncokompas' that supports cancer survivors in self-management: results of a randomised controlled trial.

J Cancer Surviv 2021 Feb 12;15(1):77-86. Epub 2020 Jul 12.

Department of Clinical, Neuro- and Developmental Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands.

Purpose: The eHealth self-management application 'Oncokompas' was developed to support cancer survivors in monitoring health-related quality of life (HRQOL) and symptoms, and obtaining personalized feedback and options for supportive care. The aim of this study was to assess the cost-utility of Oncokompas compared with care as usual (CAU) among cancer survivors.

Methods: Survivors were randomly allocated to the intervention or control group. Direct (non-)medical, indirect non-medical costs, and HRQOL were measured at 3- and 6-month follow-up, using iMTA Medical Consumption and Productivity Costs and the EuroQol-5D questionnaires. Mean cumulative costs and quality-adjusted life-years (QALYs) were compared between both groups.

Results: In total, 625 survivors were randomized into intervention (n = 320) or control group (n = 305). Base case analysis showed that incremental costs from a societal perspective were - €163 (95% CI, - 665 to 326), and incremental QALYs were 0.0017 (95% CI, - 0.0121 to 0.0155) in the intervention group compared with those in the control group. The probability that, compared with CAU, Oncokompas is more effective was 60%, less costly 73%, and both more effective and less costly 47%. Sensitivity analyses showed that incremental costs vary between - €40 and €69, and incremental QALYs vary between - 0.0023 and - 0.0057.

Conclusion: Oncokompas is likely to be equally effective on utilities, and not more expensive than CAU, and will therefore contribute to sustainable cancer survivorship care in a (cost-)effective manner.

Implications For Cancer Survivors: Oncokompas seems to improve HRQOL and reduces the burden of several tumour-specific symptoms, while costs from a societal perspective are similar to CAU.
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http://dx.doi.org/10.1007/s11764-020-00912-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822793PMC
February 2021

Elective Neck Dissection or Sentinel Lymph Node Biopsy in Early Stage Oral Cavity Cancer Patients: The Dutch Experience.

Cancers (Basel) 2020 Jul 3;12(7). Epub 2020 Jul 3.

Department of Head and Neck Surgical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.

Background: Sentinel lymph node biopsy (SLNB) has been introduced as a diagnostic staging modality for detection of occult metastases in patients with early stage oral cancer. Comparisons regarding accuracy to the routinely used elective neck dissection (END) are lacking in literature.

Methods: A retrospective, multicenter cohort study included 390 patients staged by END and 488 by SLNB.

Results: The overall sensitivity (84% vs. 81%, = 0.612) and negative predictive value (NPV) (93%, = 1.000) were comparable between END and SLNB patients. The END cohort contained more pT2 tumours (51%) compared to the SLNB cohort (23%) ( < 0.001). No differences were found for sensitivity and NPV between SLNB and END divided by pT stage. In floor-of-mouth (FOM) tumours, SLNB had a lower sensitivity (63% vs. 92%, = 0.006) and NPV (90% vs. 97%, = 0.057) compared to END. Higher disease-specific survival (DSS) rates were found for pT1 SLNB patients compared to pT1 END patients (96% vs. 90%, = 0.048).

Conclusion: In the absence of randomized clinical trials, this study provides the highest available evidence that, in oral cancer, SLNB is as accurate as END in detecting occult lymph node metastases, except for floor-of-mouth tumours.
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http://dx.doi.org/10.3390/cancers12071783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407164PMC
July 2020

The Immune Microenvironment in Head and Neck Squamous Cell Carcinoma: on Subsets and Subsites.

Curr Oncol Rep 2020 06 29;22(8):81. Epub 2020 Jun 29.

Department of Otolaryngology-Head and Neck Surgery, Cancer Center Amsterdam, Amsterdam UMC, VU University medical center, De Boelelaan, 1117, Amsterdam, The Netherlands.

Purpose: To understand why some patients respond to immunotherapy but many do not, a clear picture of the tumor microenvironment (TME) of head and neck squamous cell carcinoma (HNSCC) is key. Here we review the current understanding on the immune composition per HNSCC subsite, the importance of the tumor's etiology and the prognostic power of specific immune cells.

Recent Findings: Large cohort data are mostly based on deconvolution of transcriptional databases. Studies focusing on infiltrate localization often entail small cohorts, a mixture of HNSCC subsites, or focus on a single immune marker rather than the interaction between cells within the TME. Conclusions on the prognostic impact of specific immune cells in HNSCC are hampered by the use of heterogeneous or small cohorts. To move forward, the field should focus on deciphering the immune composition per HNSCC subsite, in powered cohorts and considering the molecular diversity in this disease.
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http://dx.doi.org/10.1007/s11912-020-00938-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324425PMC
June 2020

Comprehensive multiparameter genetic analysis improves circulating tumor DNA detection in head and neck cancer patients.

Oral Oncol 2020 Jun 23;109:104852. Epub 2020 Jun 23.

Department of Otolaryngology - Head and Neck Surgery, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, the Netherlands. Electronic address:

Introduction: Tumor-specific genetic aberrations in cell-free DNA (cfDNA) from plasma are promising biomarkers for diagnosis of recurrent head and neck squamous cell carcinoma (HNSCC). However, the sensitivity when using somatic mutations only in cfDNA is suboptimal. Here, we combined detection of copy number aberrations (CNAs), human papillomavirus (HPV) DNA and somatic mutations in a single sequencing workflow.

Methods: Pretreatment plasmas of 40 patients and 20 non-cancer controls were used for analysis. Plasma DNA underwent low-coverage whole genome sequencing (lcWGS) to detect both CNAs and HPV-DNA, and deep sequencing to detect mutations in 12 frequently altered cancer driver genes in HNSCC using the same sequencing library. A specific analysis pipeline line was developed for data mining. The corresponding tumors were analyzed using slightly adapted protocols.

Results: Using the developed method, somatic mutations and CNAs were detected in plasma DNA of HNSCC patients in 67% and 52%, respectively. HPV-DNA in plasma was detected in 100% of patients with HPV-positive tumors, and not in plasma of patients with HPV-negative tumors or non-cancer controls. Combined analysis increased the detection rate of tumor DNA in plasma to 78%. The detection rate was significantly associated with the stage of disease of the tumor. Neither HPV status nor location of the primary tumor influenced detection of CNAs or somatic mutations in plasma.

Conclusions: This study demonstrates that the combined analysis of CNAs, HPV and somatic mutations in plasma of HNSCC patients is feasible and contributes to a higher sensitivity of the assay compared to single modality analyses.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104852DOI Listing
June 2020

Comparison of Carboplatin With 5-Fluorouracil vs. Cisplatin as Concomitant Chemoradiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma.

Front Oncol 2020 5;10:761. Epub 2020 Jun 5.

Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Chemoradiotherapy (CRT) including three cycles of cisplatin is considered the standard of care for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, around one-third of the patients cannot complete cisplatin because of toxicity. Carboplatin plus 5-fluorouracil (carbo-5FU) is another accepted treatment option with a different toxicity profile. We compared tolerability and efficacy of concomitant carbo-5FU and cisplatin. We conducted a retrospective analysis of LA-HNSCC patients treated with CRT in two Dutch cancer centers between 2007 and 2016. All patients received intensity-modulated radiotherapy. One center routinely administered carboplatin 300-350 mg/m at day 1, 22, and 43 followed by 5FU 600 mg/m/day for 96 h. The other center used cisplatin 100 mg/m at day 1, 22, and 43. The primary endpoint of this study was chemotherapy completion rate. Secondary endpoints included overall survival (OS), disease-free survival (DFS), locoregional control (LRC) and distant metastasis-free interval (DMFS), toxicity, and unplanned admissions. In the carbo-5FU cohort ( = 211), 60.2% of the patients completed chemotherapy vs. 76.7% ( < 0.001) of the patients in the cisplatin cohort ( = 223). Univariate analysis showed a higher risk of death in the carbo-5FU cohort [hazard ratio (HR) 1.53, 95% CI, 1.09-2.14, = 0.01] with a 3-year OS of 65.4 vs. 76.5% for cisplatin. OS was independently associated with T and N stage and p16 status, but not with chemotherapy regimen (HR 1.08, 95% CI, 0.76-1.55, = 0.65). Three-year DFS was 70.0% for carbo-5FU vs. 78.6% for cisplatin (HR 1.37, 95% CI, 0.93-2.01, = 0.05). A similar outcome was observed for both LRC (HR 1.27, 95% CI, 0.74-2.09, = 0.4) and DMFS (HR 1.08, 95% CI 0.62-1.90, = 0.77). The risk of discontinuation for chemotherapy-associated toxicity was higher in the carbo-5FU cohort than in the cisplatin cohort (relative risk = 1.69). LA-HNSCC patients treated with concomitant carbo-5FU completed chemotherapy less frequently than patients treated with cisplatin. Treatment regimen was not an independent prognostic factor for OS.
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http://dx.doi.org/10.3389/fonc.2020.00761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292049PMC
June 2020

Poor sleep quality among newly diagnosed head and neck cancer patients: prevalence and associated factors.

Support Care Cancer 2021 Feb 22;29(2):1035-1045. Epub 2020 Jun 22.

Department of Clinical, Neuro- and Developmental Psychology, Faculty of Behavioural and Movement Sciences & Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands.

Background: Head and neck cancer (HNC) patients often suffer from distress attributed to their cancer diagnosis which may disturb their sleep. However, there is lack of research about poor sleep quality among newly diagnosed HNC patients. Therefore, our aim was to investigate the prevalence and the associated factors of poor sleep quality among HNC patients before starting treatment.

Materials And Methods: A cross-sectional study was conducted using the baseline data from NET-QUBIC study, an ongoing multi-center cohort of HNC patients in the Netherlands. Poor sleep quality was defined as a Pittsburgh Sleep Quality Index (PSQI) total score of > 5. Risk factors examined were sociodemographic factors (age, sex, education level, living situation), clinical characteristics (HNC subsite, tumor stage, comorbidity, performance status), lifestyle factors, coping styles, and HNC symptoms.

Results: Among 560 HNC patients, 246 (44%) had poor sleep quality before start of treatment. Several factors were found to be significantly associated with poor sleep: younger age (odds ratio [OR] for each additional year 0.98, 95% CI 0.96-1.00), being female (OR 2.6, 95% CI 1.7-4.1), higher passive coping style (OR 1.18, 95% CI 1.09-1.28), more oral pain (OR 1.10, 95% CI 1.01-1.19), and less sexual interest and enjoyment (OR 1.13, 95% CI 1.06-1.20).

Conclusion: Poor sleep quality is highly prevalent among HNC patients before start of treatment. Early evaluation and tailored intervention to improve sleep quality are necessary to prepare these patients for HNC treatment and its consequences.
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http://dx.doi.org/10.1007/s00520-020-05577-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767896PMC
February 2021

Recommendations for head and neck surgical oncology practice in a setting of acute severe resource constraint during the COVID-19 pandemic: an international consensus.

Lancet Oncol 2020 07 11;21(7):e350-e359. Epub 2020 Jun 11.

Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University, Palo Alto, CA, USA.

The speed and scale of the global COVID-19 pandemic has resulted in unprecedented pressures on health services worldwide, requiring new methods of service delivery during the health crisis. In the setting of severe resource constraint and high risk of infection to patients and clinicians, there is an urgent need to identify consensus statements on head and neck surgical oncology practice. We completed a modified Delphi consensus process of three rounds with 40 international experts in head and neck cancer surgical, radiation, and medical oncology, representing 35 international professional societies and national clinical trial groups. Endorsed by 39 societies and professional bodies, these consensus practice recommendations aim to decrease inconsistency of practice, reduce uncertainty in care, and provide reassurance for clinicians worldwide for head and neck surgical oncology in the context of the COVID-19 pandemic and in the setting of acute severe resource constraint and high risk of infection to patients and staff.
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http://dx.doi.org/10.1016/S1470-2045(20)30334-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289563PMC
July 2020

Outcome prediction of head and neck squamous cell carcinoma by MRI radiomic signatures.

Eur Radiol 2020 Nov 4;30(11):6311-6321. Epub 2020 Jun 4.

Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

Objectives: Head and neck squamous cell carcinoma (HNSCC) shows a remarkable heterogeneity between tumors, which may be captured by a variety of quantitative features extracted from diagnostic images, termed radiomics. The aim of this study was to develop and validate MRI-based radiomic prognostic models in oral and oropharyngeal cancer.

Materials And Methods: Native T1-weighted images of four independent, retrospective (2005-2013), patient cohorts (n = 102, n = 76, n = 89, and n = 56) were used to delineate primary tumors, and to extract 545 quantitative features from. Subsequently, redundancy filtering and factor analysis were performed to handle collinearity in the data. Next, radiomic prognostic models were trained and validated to predict overall survival (OS) and relapse-free survival (RFS). Radiomic features were compared to and combined with prognostic models based on standard clinical parameters. Performance was assessed by integrated area under the curve (iAUC).

Results: In oral cancer, the radiomic model showed an iAUC of 0.69 (OS) and 0.70 (RFS) in the validation cohort, whereas the iAUC in the oropharyngeal cancer validation cohort was 0.71 (OS) and 0.74 (RFS). By integration of radiomic and clinical variables, the most accurate models were defined (iAUC oral cavity, 0.72 (OS) and 0.74 (RFS); iAUC oropharynx, 0.81 (OS) and 0.78 (RFS)), and these combined models outperformed prognostic models based on standard clinical variables only (p < 0.001).

Conclusions: MRI radiomics is feasible in HNSCC despite the known variability in MRI vendors and acquisition protocols, and radiomic features added information to prognostic models based on clinical parameters.

Key Points: • MRI radiomics can predict overall survival and relapse-free survival in oral and HPV-negative oropharyngeal cancer. • MRI radiomics provides additional prognostic information to known clinical variables, with the best performance of the combined models. • Variation in MRI vendors and acquisition protocols did not influence performance of radiomic prognostic models.
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http://dx.doi.org/10.1007/s00330-020-06962-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554007PMC
November 2020

Computed tomography-derived radiomic signature of head and neck squamous cell carcinoma (peri)tumoral tissue for the prediction of locoregional recurrence and distant metastasis after concurrent chemo-radiotherapy.

PLoS One 2020 22;15(5):e0232639. Epub 2020 May 22.

The D-lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.

Introduction: In this study, we investigate the role of radiomics for prediction of overall survival (OS), locoregional recurrence (LRR) and distant metastases (DM) in stage III and IV HNSCC patients treated by chemoradiotherapy. We hypothesize that radiomic analysis of (peri-)tumoral tissue may detect invasion of surrounding tissues indicating a higher chance of locoregional recurrence and distant metastasis.

Methods: Two comprehensive data sources were used: the Dutch Cancer Society Database (Alp 7072, DESIGN) and "Big Data To Decide" (BD2Decide). The gross tumor volumes (GTV) were delineated on contrast-enhanced CT. Radiomic features were extracted using the RadiomiX Discovery Toolbox (OncoRadiomics, Liege, Belgium). Clinical patient features such as age, gender, performance status etc. were collected. Two machine learning methods were chosen for their ability to handle censored data: Cox proportional hazards regression and random survival forest (RSF). Multivariable clinical and radiomic Cox/ RSF models were generated based on significance in univariable cox regression/ RSF analyses on the held out data in the training dataset. Features were selected according to a decreasing hazard ratio for Cox and relative importance for RSF.

Results: A total of 444 patients with radiotherapy planning CT-scans were included in this study: 301 head and neck squamous cell carcinoma (HNSCC) patients in the training cohort (DESIGN) and 143 patients in the validation cohort (BD2DECIDE). We found that the highest performing model was a clinical model that was able to predict distant metastasis in oropharyngeal cancer cases with an external validation C-index of 0.74 and 0.65 with the RSF and Cox models respectively. Peritumoral radiomics based prediction models performed poorly in the external validation, with C-index values ranging from 0.32 to 0.61 utilizing both feature selection and model generation methods.

Conclusion: Our results suggest that radiomic features from the peritumoral regions are not useful for the prediction of time to OS, LR and DM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232639PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244120PMC
August 2020

Update on oral and oropharyngeal cancer staging - International perspectives.

World J Otorhinolaryngol Head Neck Surg 2020 Mar 6;6(1):66-75. Epub 2020 Mar 6.

Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA.

Squamous cell carcinoma of the oral cavity and oropharynx have been used synonymously and interchangeably in the world literature in the context of head and neck cancers. As the 21st century progresses, divergence between the two have become more evident, particularly due to evidence related to human papillomavirus-associated oropharyngeal squamous cell carcinoma. As such, the American Joint Committee on Cancer recently published the 8th edition Cancer Staging Manual, serving as a continued global resource to clinicians and researchers. Through changes in staging related to T and N clinical and pathologic classifications, the new system is expected to influence current management guidelines of these cancers that have distinct anatomic and etiopathogenic characteristics. This article aims to review such impactful changes in a time of critical transition of the staging of head and neck cancer and how these changes may affect clinicians and researchers worldwide.
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http://dx.doi.org/10.1016/j.wjorl.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221211PMC
March 2020

Epithelial-to-mesenchymal transition is a prognostic marker for patient outcome in advanced stage HNSCC patients treated with chemoradiotherapy.

Radiother Oncol 2020 Jun 13;147:186-194. Epub 2020 May 13.

Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address:

Background: The prognosis of patients with HPV-negative advanced stage head and neck squamous cell carcinoma (HNSCC) remains poor. No prognostic markers other than TNM staging are routinely used in clinic. Epithelial-to-mesenchymal transition (EMT) has been shown to be a strong prognostic factor in other cancer types. The purpose of this study was to determine the role of EMT in HPV-negative HNSCC outcomes.

Methods: Pretreatment tumor material from patients of two cohorts, totalling 174 cisplatin-based chemoradiotherapy treated HPV-negative HNSCC patients, was RNA-sequenced. Seven different EMT gene expression signatures were used for EMT status classification and generation of HNSCC-specific EMT models using Random Forest machine learning.

Results: Mesenchymal classification by all EMT signatures consistently enriched for poor prognosis patients in both cohorts of 98 and 76 patients. Uni- and multivariate analyses show important HR of 1.6-5.8, thereby revealing EMT's role in HNSCC outcome. Discordant classification by these signatures prompted the generation of an HNSCC-specific EMT profile based on the concordantly classified samples in the first cohort (cross-validation AUC > 0.98). The independent validation cohort confirmed the association of mesenchymal classification by the HNSCC-EMT model with poor overall survival (HR = 3.39, p < 0.005) and progression free survival (HR = 3.01, p < 0.005) in multivariate analysis with TNM. Analysis of an additional HNSCC cohort from PET-positive patients with metastatic disease prior to treatment further supports this relationship and reveals a strong link of EMT to the propensity to metastasize.

Conclusions: EMT in HPV-negative HNSCC co-defines patient outcome after chemoradiotherapy. The generated HNSCC-EMT prediction models can function as strong prognostic biomarkers.
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http://dx.doi.org/10.1016/j.radonc.2020.05.013DOI Listing
June 2020