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Papers by Robert de Jong

Research paper thumbnail of Resection margins in oral cancer surgery: Room for improvement

Head & neck, Jun 15, 2015

Chapter 1 General introduction Chapter 2 Resection margins in oral cancer surgery: room for impro... more Chapter 1 General introduction Chapter 2 Resection margins in oral cancer surgery: room for improvement.

Research paper thumbnail of Development and Assessment of a Model for Predicting Individualized Outcomes in Patients With Oropharyngeal Cancer

JAMA Network Open

IMPORTANCE Recent insights into the biologic characteristics and treatment of oropharyngeal cance... more IMPORTANCE Recent insights into the biologic characteristics and treatment of oropharyngeal cancer may help inform improvements in prognostic modeling. A bayesian multistate model incorporates sophisticated statistical techniques to provide individualized predictions of survival and recurrence outcomes for patients with newly diagnosed oropharyngeal cancer. OBJECTIVE To develop a model for individualized survival, locoregional recurrence, and distant metastasis prognostication for patients with newly diagnosed oropharyngeal cancer, incorporating clinical, oncologic, and imaging data. DESIGN, SETTING, AND PARTICIPANTS In this prognostic study, a data set was used comprising 840 patients with newly diagnosed oropharyngeal cancer treated at a National Cancer Institutedesignated center between January 2003 and August 2016; analysis was performed between January 2019 and June 2020. Using these data, a bayesian multistate model was developed that can be used to obtain individualized predictions. The prognostic performance of the model was validated using data from 447 patients treated for oropharyngeal cancer at Erasmus Medical Center in the Netherlands. EXPOSURES Clinical/oncologic factors and imaging biomarkers collected at or before initiation of firstline therapy. MAIN OUTCOMES AND MEASURES Overall survival, locoregional recurrence, and distant metastasis after first-line cancer treatment. RESULTS Of the 840 patients included in the National Cancer Institute-designated center, 715 (85.1%) were men and 268 (31.9%) were current smokers. The Erasmus Medical Center cohort comprised 300 (67.1%) men, with 350 (78.3%) current smokers. Model predictions for 5-year overall survival demonstrated good discrimination, with area under the curve values of 0.81 for the model with and 0.78 for the model without imaging variables. Application of the model without imaging data in the independent Dutch validation cohort resulted in an area under the curve of 0.75. This model possesses good calibration and stratifies patients well in terms of likely outcomes among many competing events. CONCLUSIONS AND RELEVANCE In this prognostic study, a multistate model of oropharyngeal cancer incorporating imaging biomarkers appeared to estimate and discriminate locoregional recurrence from distant metastases. Providing personalized predictions of multiple outcomes increases the information available for patients and clinicians. The web-based application designed (continued) Key Points Question Can a model be developed for individualized survival, locoregional recurrence, and distant metastasis prognostication for patients newly diagnosed with oropharyngeal cancer, incorporating clinical, oncologic, and imaging data? Findings In this prognostic study, model predictions for 5-year overall survival demonstrated excellent discrimination in cohort study training data for models with and without imaging variables. This model appeared to possess good calibration and well stratified patients in terms of likely outcomes among many competing events. Meaning This prognostic model and web-based application may serve as a useful tool to provide clinicians, researchers, and patients with oropharyngeal cancer robust, individualized prognostic estimations.

Research paper thumbnail of The course of swallowing problems in the first 2 years after diagnosis of head and neck cancer

Supportive Care in Cancer

Introduction Head and neck cancer (HNC) and its treatment often negatively impact swallowing func... more Introduction Head and neck cancer (HNC) and its treatment often negatively impact swallowing function. The aim was to investigate the course of patient-reported swallowing problems from diagnosis to 3, 6, 12, and 24 months after treatment, in relation to demographic, clinical, and lifestyle factors. Methods Data were used of the Netherlands Quality of Life and Biomedical Cohort Study in head and neck cancer research (NET-QUBIC). The primary outcome measures were the subscales of the Swallowing Quality of Life Questionnaire (SWAL-QOL). Linear mixed-effects models (LMM) were conducted to investigate changes over time and associations with patient, clinical, and lifestyle parameters as assessed at baseline. Results Data were available of 603 patients. There was a significant change over time on all subscales. Before treatment, 53% of patients reported swallowing problems. This number increased to 70% at M3 and decreased to 59% at M6, 50% at M12, and 48% at M24. Swallowing problems (i.e...

Research paper thumbnail of A cause‐specific Cox model for second primary tumors in patients with head and neck cancer: A RONCDOC study

Head & Neck, 2021

BackgroundThe aim of this study was to identify risk factors for the development of second primar... more BackgroundThe aim of this study was to identify risk factors for the development of second primary tumors (SPTs) in the head and neck region, lungs, and esophagus in patients with head and neck cancer.MethodsWe collected data from 1581 patients. A cause‐specific Cox model for the development of an SPT was fitted, accounting for the competing risks residual/recurrent tumor and mortality.ResultsOf all patients, 246 (15.6%) developed SPTs. Analysis showed that tobacco and alcohol use, comorbidity, and the oral cavity subsite were risk factors for SPTs. The C‐index, the discriminative accuracy, of the model for SPT was 0.65 (95% confidence interval, 0.61–0.68).ConclusionsOur results show that there is potential to identify patients who have an increased risk to develop an SPT. This might increase their survival chances and quality of life. More research is needed to provide head and neck clinicians with definitive recommendations.

Research paper thumbnail of Screening for synchronous esophageal second primary tumors in patients with head and neck cancer

Diseases of the Esophagus, 2021

Summary Patients with head and neck squamous cell carcinoma (HNSCC) have an increased risk of dev... more Summary Patients with head and neck squamous cell carcinoma (HNSCC) have an increased risk of developing esophageal second primary tumors (ESPTs). We aimed to determine the incidence, stage, and outcome of synchronous ESPTs in patients with HNSCC in a Western population. We performed a prospective, observational, and cohort study. Patients diagnosed with HNSCC in the oropharynx, hypopharynx, any other sub-location in combination with alcohol abuse, or patients with two synchronous HNSCCs, between February 2019 and February 2020 underwent screening esophagogastroduodenoscopy (EGD). ESPT was defined as presence of esophageal squamous cell carcinoma (ESCC) or high grade dysplasia (HGD). Eighty-five patients were included. A lesion suspected for ESPT was detected in 14 of 85 patients, which was pathologically confirmed in five patients (1 ESCC and 4 HGD). The radiotherapy field was extended to the esophagus in two of five patients, HGD was treated with endoscopic resection in three of f...

Research paper thumbnail of Intraoperative Assessment of the Resection Specimen Facilitates Achievement of Adequate Margins in Oral Carcinoma

Frontiers in Oncology, 2020

BackgroundInadequate resection margins in oral cavity squamous cell carcinoma have an adverse eff... more BackgroundInadequate resection margins in oral cavity squamous cell carcinoma have an adverse effect on patient outcome. Intraoperative assessment provides immediate feedback enabling the surgeon to achieve adequate resection margins. The goal of this study was to evaluate the value of specimen-driven intraoperative assessment by comparing the margin status in the period before and the period after the introduction of specimen-driven assessment as a standard of care (period 2010–2012 vs period 2013–2017).MethodsA cohort of patients surgically treated for oral squamous cell carcinoma at the Erasmus MC Cancer Institute, Rotterdam, between 2010–2012 was studied retrospectively and compared to results of a prospectively collected cohort between 2013–2017. The frequency, type and results of intraoperative assessment of resection margins were analyzed.ResultsOne hundred seventy-four patients were included from 2010–2012, 241 patients were included from 2013–2017. An increase in the freque...

Research paper thumbnail of Is the Depth of Invasion a Marker for Elective Neck Dissection in Early Oral Squamous Cell Carcinoma?

Frontiers in Oncology, 2021

ObjectiveThe depth of invasion (DOI) is considered an independent risk factor for occult lymph no... more ObjectiveThe depth of invasion (DOI) is considered an independent risk factor for occult lymph node metastasis in oral cavity squamous cell carcinoma (OCSCC). It is used to decide whether an elective neck dissection (END) is indicated in the case of a clinically negative neck for early stage carcinoma (pT1/pT2). However, there is no consensus on the cut-off value of the DOI for performing an END. The aim of this study was to determine a cut-off value for clinical decision making on END, by assessing the association of the DOI and the risk of occult lymph node metastasis in early OCSCC.MethodsA retrospective cohort study was conducted at the Erasmus MC, University Medical Centre Rotterdam, The Netherlands. Patients surgically treated for pT1/pT2 OCSCC between 2006 and 2012 were included. For all cases, the DOI was measured according to the 8th edition of the American Joint Committee on Cancer guideline. Patient characteristics, tumor characteristics (pTN, differentiation grade, perin...

Research paper thumbnail of The unveiled reality of human papillomavirus as risk factor for oral cavity squamous cell carcinoma

International Journal of Cancer, 2021

The prognostic impact of human papillomavirus (HPV) in oropharyngeal cancer is generally acknowle... more 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 to detect HPV in nonoropharyngeal cancers, the relatively small cohorts studied and consequently the shortfall of convincing data. In our study, we used a validated, nucleic acid‐based workflow to assess HPV‐prevalence in a consecutive cohort of 1016 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 and 2014 at two Dutch university medical centers were included (N = 1069). For...

Research paper thumbnail of Current Intraoperative Imaging Techniques to Improve Surgical Resection of Laryngeal Cancer: A Systematic Review

Cancers, 2021

Laryngeal cancer is a prevalent head and neck malignancy, with poor prognosis and low survival ra... more Laryngeal cancer is a prevalent head and neck malignancy, with poor prognosis and low survival rates for patients with advanced disease. Treatment consists of unimodal therapy through surgery or radiotherapy in early staged tumors, while advanced stage tumors are generally treated with multimodal chemoradiotherapy or (total) laryngectomy followed by radiotherapy. Still, the recurrence rate for advanced laryngeal cancer is between 25 and 50%. In order to improve surgical resection of laryngeal cancer and reduce local recurrence rates, various intraoperative optical imaging techniques have been investigated. In this systematic review, we identify these technologies, evaluating the current state and future directions of optical imaging for this indication. Narrow-band imaging (NBI) and autofluorescence (AF) are established tools for early detection of laryngeal cancer. Nonetheless, their intraoperative utility is limited by an intrinsic inability to image beyond the (sub-)mucosa. Likew...

Research paper thumbnail of Increased risk of second primary tumours in patients with oesophageal squamous cell carcinoma: a nationwide study in a Western population

United European Gastroenterology Journal, 2021

BackgroundPatients with primary oesophageal squamous cell carcinoma are at risk of developing mul... more BackgroundPatients with primary oesophageal squamous cell carcinoma are at risk of developing multiple primary tumours in the upper aero digestive tract. To date, most studies are performed in the Asian population. We aimed to evaluate the risk of multiple primary tumours in the upper aero digestive tract and stomach in patients with oesophageal squamous cell carcinoma in a Western population.MethodsWe performed a nationwide, retrospective cohort study in collaboration with the Netherlands Cancer Registry. Patients with primary oesophageal squamous cell carcinoma, diagnosed between 2000 and 2016, were included. Primary endpoints were synchronous and metachronous multiple primary tumour risk.ResultsThe cohort consisted of 9058 patients, diagnosed with oesophageal squamous cell carcinoma (male: 57.3%, median age 67 years). In 476 patients (5.3%), 545 multiple primary tumours have been diagnosed. Most of them were located in the head and neck region (49.5%). Among all multiple primary ...

Research paper thumbnail of Intraoperative Assessment of Resection Margins in Oral Cavity Cancer: This is the Way

Journal of Visualized Experiments

The goal of head and neck oncological surgery is complete tumor resection with adequate resection... more The goal of head and neck oncological surgery is complete tumor resection with adequate resection margins while preserving acceptable function and appearance. For oral cavity squamous cell carcinoma (OCSCC), different studies showed that only 15%-26% of all resections are adequate. A major reason for the low number of adequate resections is the lack of information during surgery; the margin status is only available after the final histopathologic assessment, days after surgery. The surgeons and pathologists at the Erasmus MC University Medical Center in Rotterdam started the implementation of specimen-driven intraoperative assessment of resection margins (IOARM) in 2013, which became the standard of care in 2015. This method enables the surgeon to turn an inadequate resection into an adequate resection by performing an additional resection during the initial surgery. Intraoperative assessment is supported by a relocation method procedure that allows accurate identification of inadequate margins (found on the specimen) in the wound bed. The implementation of this protocol resulted in an improvement of adequate resections from 15%-40%. However, the specimen-driven IOARM is not widely adopted because grossing fresh tissue is counter-intuitive for pathologists. The fear exists that grossing fresh tissue will deteriorate the anatomical orientation, shape, and size of the specimen and therefore will affect the final histopathologic assessment. These possible negative effects are countered by the described protocol. Here, the protocol for specimen-driven IOARM is presented in detail, as performed at the institute.

Research paper thumbnail of A novel immunohistochemical scoring system reveals associations of C-terminal MET, ectodomain shedding, and loss of E-cadherin with poor prognosis in oral squamous cell carcinoma

Human Pathology, 2020

Take-down policy If you believe that this document breaches copyright please contact us providing... more Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Research paper thumbnail of Absent and abundant MET immunoreactivity is associated with poor prognosis of patients with oral and oropharyngeal squamous cell carcinoma

Oncotarget, 2016

Although the receptor tyrosine kinase (RTK) MET is widely expressed in head and neck squamous cel... more Although the receptor tyrosine kinase (RTK) MET is widely expressed in head and neck squamous cell carcinoma (HNSCC), its prognostic value remains unclear. This might be due to the use of a variety of antibodies and scoring systems. Here, the reliability of five commercial C-terminal MET antibodies (D1C2, CVD13, SP44, C-12 and C-28) was evaluated before examining the prognostic value of MET immunoreactivity in HNSCC. Using cancer cell lines, it was shown that D1C2 and CVD13 specifically detect MET under reducing, native and formalin-fixed paraffin-embedded (FFPE) conditions. Immunohistochemical staining of routinely FFPE oral SCC with D1C2 and CVD13 demonstrated that D1C2 is most sensitive in the detection of membranous MET. Examination of membranous D1C2 immunoreactivity with 179 FFPE oral and oropharyngeal SCC-represented in a tissue microarray-illustrated that staining is either uniform (negative or positive) across tumors or differs between a tumor's center and periphery. Ultimately, statistical analysis revealed that D1C2 uniform staining is significantly associated with poor 5-year overall and disease free survival of patients lacking vasoinvasive growth (HR = 3.019, p < 0.001; HR = 2.559, p < 0.001). These findings might contribute to reliable stratification of patients eligible for treatment with biologicals directed against MET.

Research paper thumbnail of The potential use of big data in oncology

Oral Oncology, 2019

In this era of information technology, big data analysis is entering biomedical sciences. But wha... more In this era of information technology, big data analysis is entering biomedical sciences. But what is big data, where do they come from and what can we do with it? In this commentary, the main sources of big data are explained, especially in (head and neck) oncology. It also touches upon the need to integrate various sources of clinical, pathological and quality-of-life data. It discusses some initiatives in linking of such datasets on a nationwide scale in the Netherlands. Finally, it touches upon important issues regarding governance, FAIRness of data and the need to bring into place the necessary infrastructures needed to fully exploit the full potential of big data sets in head and neck cancer.

Research paper thumbnail of Towards the Optical Detection of Field Cancerization in the Buccal Mucosa of Patients with Lung Cancer

Translational Oncology, 2019

INTRODUCTION: An increase in detection of early-stage asymptomatic lung tumors could increase the... more INTRODUCTION: An increase in detection of early-stage asymptomatic lung tumors could increase the overall survival rate of lung cancer patients. A new approach to cancer (pre-)screening focusses on detecting field cancerization instead of the tumor itself. The objective of this study was to investigate the use of optical spectroscopy to detect field cancerization in the buccal mucosa of lung cancer patients. METHODS: Optical buccal mucosa measurements were performed in lung cancer patients and controls using multidiameter single-fiber reflectance spectroscopy. We analyzed whether the measured optical parameters could distinguish lung cancer patients from controls. RESULTS: Twenty-three lung cancer patients, 24 chronic obstructive pulmonary disease (COPD) control patients, and 36 non-COPD controls were included. The majority of tumors were non-small-cell lung carcinomas (96%) and classified as stage I (48%). The tissue scattering properties m s ' and g at 800 nm and the tissue bilirubin concentration were all near-significantly different (P ¼ .072, 0.058, and 0.060, respectively) between the lung cancer and COPD group. m s ' at 800 nm had a sensitivity of 74% and a specificity of 63%. The microvascular blood oxygen saturation of the lung cancer patients was also higher than the COPD patients (78% vs. 62%, P ¼ .002), this is probably a consequence of the systemic effect of COPD. CONCLUSIONS: We have demonstrated that m s ' at 800 nm is increased in the buccal mucosa of patients with lung cancer compared to controls with COPD. This might be an indication of field cancerization in the oral cavity of patients with lung cancer.

Research paper thumbnail of Relocation of inadequate resection margins in the wound bed during oral cavity oncological surgery: A feasibility study

Head & Neck, 2019

Background: Specimen-driven intraoperative assessment of the resection margins provides immediate... more Background: Specimen-driven intraoperative assessment of the resection margins provides immediate feedback if an additional excision is needed. However, relocation of an inadequate margin in the wound bed has shown to be difficult. The objective of this study is to assess a reliable method for accurate relocation of inadequate tumor resection margins in the wound bed after intraoperative assessment of the specimen. Methods: During oral cavity cancer surgery, the surgeon placed numbered tags on both sides of the resection line in a pair-wise manner. After resection, one tag of each pair remained on the specimen and the other tag in the wound bed. Upon detection of an inadequate margin in the specimen, the tags were used to relocate this margin in the wound bed. Results: The method was applied during 80 resections for oral cavity cancer. In 31 resections an inadequate margin was detected, and based on the paired tagging an accurate additional resection was achieved. Conclusion: Paired tagging facilitates a reliable relocation of inadequate margins, enabling an accurate additional resection during the initial surgery.

Research paper thumbnail of Screening for Head and Neck Second Primary Tumors in Patients with Esophageal Squamous Cell Cancer: A Systematic Review and Meta-Analysis

ESGE Days 2019, 2019

Background: Esophageal squamous cell carcinomas (ESCCs) are often accompanied by head and neck se... more Background: Esophageal squamous cell carcinomas (ESCCs) are often accompanied by head and neck second primary tumors (HNSPTs). The prognosis of patients with an additional HNSPT is worse compared with patients with only ESCC. Therefore, early detection of HNSPTs may improve the overall outcome of patients with ESCC. The purpose of this study was to investigate the yield of endoscopic screening for HNSPTs in patients with primary ESCC. Methods: We conducted a systematic literature search of all available databases. Studies were included if ESCC patients were endoscopically screened for HNSPT. The primary outcome was the pooled prevalence of HNSPTs. Results: Twelve studies, all performed in Japan, were included in this systematic review with a total of 6483 patients. The pooled prevalence of HNSPTs was 6.7% (95% confidence interval: 4.9-8.4). The overall heterogeneity was high across the studies (I 2 ¼ 89.0%, p < 0.001). Most HNSPTs were low stage (85.3%) and located in the hypopharynx (60.3%). The proportion of synchronous (48.2%) and metachronous (51.8%) HNSPTs was comparable. Conclusion: Based on our results, HNSPT screening could be considered in patients with primary ESCC. All studies were performed in Japan; it is therefore not clear whether this consideration applies to the Western world.

Research paper thumbnail of Quality of life and voice outcome of patients treated with transoral CO2 laser microsurgery for early glottic carcinoma (T1–T2): a 2-year follow-up study

European Archives of Oto-Rhino-Laryngology, 2019

Purpose Longitudinal studies in laryngeal cancer can provide clinicians information about short-t... more Purpose Longitudinal studies in laryngeal cancer can provide clinicians information about short-term and long-term functional outcomes, like quality of life (QoL) and voice outcome. This information is important when counseling patients or choosing a primary treatment modality. The present study assessed long-term (2 years) QoL and voice outcome in patients with extended T1 and limited T2 glottic carcinoma treated with transoral CO 2 laser microsurgery (TLM) (unilateral type III or bilateral type II resections). Methods Three questionnaires were administered: the Voice Handicap Index (VHI), the European Organization for Research and Treatment of Cancer (EORTC) QoL questionnaire (QLQ)-C30, the EORTC QLQ-HN35. A perceptual voice evaluation at six different time points was conducted: preoperatively, and postoperatively at 6 weeks, 3 months, 6 months, 1 year, and 2 years. Fluctuations over time were investigated. Results Sixty-one patients were included in the analysis. Patients reported high-level functioning and low symptom scores 2 years postoperatively. Gender significantly affected the VHI scores at 2 years (mean VHI scores: female 8.7 vs. male, 23.9; p = 0.023). The major improvement in VHI scores was observed within the first 6 months. The tumor stage (T1a, T1b, and T2) significantly impacted the grade (mean scores at 2 years: 1.0, 1.9, and 1.7; p = 0.001). These scores stabilized at 6 months. Conclusions Patients show good long-term QoL with low symptom scores, a low voice handicap, and mild to moderate dysphonia, 2 years postoperatively. Scores stabilize at 6 months and provide a clear indication of status at 1 and 2 years.

Research paper thumbnail of A clinicopathological study and prognostic factor analysis of 177 salivary duct carcinoma patients from The Netherlands

International Journal of Cancer, 2018

Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a... more Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a need for better prognostication and novel treatments. The aim of this national cohort study was to investigate clinical outcome, prognostic factors, androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2) expression. SDC patients diagnosed between 1990 and 2014 were identified by the Nationwide Network and Registry of Histo‐ and Cytopathology in the Netherlands (PALGA). Subsequently, medical records were evaluated and pathological diagnoses reviewed. Data were analyzed for overall survival (OS), disease‐free survival (DFS), distant metastasis‐free survival (DMFS) and prognostic factors. AR was evaluated by immunohistochemistry (IHC), HER2 by IHC and fluorescent in‐situ hybridization. A total of 177 patients were included. The median age was 65 years, 75% were male. At diagnosis, 68% presented with lymph node metastases and 6% with distant metastases. Median OS, DFS an...

Research paper thumbnail of Survival of patients with head and neck cancer with metachronous multiple primary tumors is surprisingly favorable

Head & Neck, 2019

Background: The objectives of this study are to determine the incidence and survival rate of pati... more Background: The objectives of this study are to determine the incidence and survival rate of patients with head and neck squamous cell carcinoma (HNSCC) with multiple primary tumors (MPT) in the HN-region, lung, or esophagus. Methods: Patient and tumor specific data of 1372 patients with HNSCC were collected from both the national cancer registry and patient records to ensure highquality double-checked data. Results: The total incidence of MPTs in the HN-region, lung, and esophagus in patients with HNSCC was 11% (149/1372). Patients with lung MPTs and esophageal MPTs had a significant worse 5-year survival than patients with HN-MPTs (29%, 14%, and 67%, respectively, P < 0.001). The 5-year survival rate for synchronous HN MPTs was only 25%, whereas it was surprisingly high for patients with metachronous HN MPT (85%, P < 0.001). Conclusions: One of 10 patients with HNSCC develop MPTs in the HN-region, lung, or esophagus. The 5-year survival of patients with metachronous HN MPTs was surprisingly favorable.

Research paper thumbnail of Resection margins in oral cancer surgery: Room for improvement

Head & neck, Jun 15, 2015

Chapter 1 General introduction Chapter 2 Resection margins in oral cancer surgery: room for impro... more Chapter 1 General introduction Chapter 2 Resection margins in oral cancer surgery: room for improvement.

Research paper thumbnail of Development and Assessment of a Model for Predicting Individualized Outcomes in Patients With Oropharyngeal Cancer

JAMA Network Open

IMPORTANCE Recent insights into the biologic characteristics and treatment of oropharyngeal cance... more IMPORTANCE Recent insights into the biologic characteristics and treatment of oropharyngeal cancer may help inform improvements in prognostic modeling. A bayesian multistate model incorporates sophisticated statistical techniques to provide individualized predictions of survival and recurrence outcomes for patients with newly diagnosed oropharyngeal cancer. OBJECTIVE To develop a model for individualized survival, locoregional recurrence, and distant metastasis prognostication for patients with newly diagnosed oropharyngeal cancer, incorporating clinical, oncologic, and imaging data. DESIGN, SETTING, AND PARTICIPANTS In this prognostic study, a data set was used comprising 840 patients with newly diagnosed oropharyngeal cancer treated at a National Cancer Institutedesignated center between January 2003 and August 2016; analysis was performed between January 2019 and June 2020. Using these data, a bayesian multistate model was developed that can be used to obtain individualized predictions. The prognostic performance of the model was validated using data from 447 patients treated for oropharyngeal cancer at Erasmus Medical Center in the Netherlands. EXPOSURES Clinical/oncologic factors and imaging biomarkers collected at or before initiation of firstline therapy. MAIN OUTCOMES AND MEASURES Overall survival, locoregional recurrence, and distant metastasis after first-line cancer treatment. RESULTS Of the 840 patients included in the National Cancer Institute-designated center, 715 (85.1%) were men and 268 (31.9%) were current smokers. The Erasmus Medical Center cohort comprised 300 (67.1%) men, with 350 (78.3%) current smokers. Model predictions for 5-year overall survival demonstrated good discrimination, with area under the curve values of 0.81 for the model with and 0.78 for the model without imaging variables. Application of the model without imaging data in the independent Dutch validation cohort resulted in an area under the curve of 0.75. This model possesses good calibration and stratifies patients well in terms of likely outcomes among many competing events. CONCLUSIONS AND RELEVANCE In this prognostic study, a multistate model of oropharyngeal cancer incorporating imaging biomarkers appeared to estimate and discriminate locoregional recurrence from distant metastases. Providing personalized predictions of multiple outcomes increases the information available for patients and clinicians. The web-based application designed (continued) Key Points Question Can a model be developed for individualized survival, locoregional recurrence, and distant metastasis prognostication for patients newly diagnosed with oropharyngeal cancer, incorporating clinical, oncologic, and imaging data? Findings In this prognostic study, model predictions for 5-year overall survival demonstrated excellent discrimination in cohort study training data for models with and without imaging variables. This model appeared to possess good calibration and well stratified patients in terms of likely outcomes among many competing events. Meaning This prognostic model and web-based application may serve as a useful tool to provide clinicians, researchers, and patients with oropharyngeal cancer robust, individualized prognostic estimations.

Research paper thumbnail of The course of swallowing problems in the first 2 years after diagnosis of head and neck cancer

Supportive Care in Cancer

Introduction Head and neck cancer (HNC) and its treatment often negatively impact swallowing func... more Introduction Head and neck cancer (HNC) and its treatment often negatively impact swallowing function. The aim was to investigate the course of patient-reported swallowing problems from diagnosis to 3, 6, 12, and 24 months after treatment, in relation to demographic, clinical, and lifestyle factors. Methods Data were used of the Netherlands Quality of Life and Biomedical Cohort Study in head and neck cancer research (NET-QUBIC). The primary outcome measures were the subscales of the Swallowing Quality of Life Questionnaire (SWAL-QOL). Linear mixed-effects models (LMM) were conducted to investigate changes over time and associations with patient, clinical, and lifestyle parameters as assessed at baseline. Results Data were available of 603 patients. There was a significant change over time on all subscales. Before treatment, 53% of patients reported swallowing problems. This number increased to 70% at M3 and decreased to 59% at M6, 50% at M12, and 48% at M24. Swallowing problems (i.e...

Research paper thumbnail of A cause‐specific Cox model for second primary tumors in patients with head and neck cancer: A RONCDOC study

Head & Neck, 2021

BackgroundThe aim of this study was to identify risk factors for the development of second primar... more BackgroundThe aim of this study was to identify risk factors for the development of second primary tumors (SPTs) in the head and neck region, lungs, and esophagus in patients with head and neck cancer.MethodsWe collected data from 1581 patients. A cause‐specific Cox model for the development of an SPT was fitted, accounting for the competing risks residual/recurrent tumor and mortality.ResultsOf all patients, 246 (15.6%) developed SPTs. Analysis showed that tobacco and alcohol use, comorbidity, and the oral cavity subsite were risk factors for SPTs. The C‐index, the discriminative accuracy, of the model for SPT was 0.65 (95% confidence interval, 0.61–0.68).ConclusionsOur results show that there is potential to identify patients who have an increased risk to develop an SPT. This might increase their survival chances and quality of life. More research is needed to provide head and neck clinicians with definitive recommendations.

Research paper thumbnail of Screening for synchronous esophageal second primary tumors in patients with head and neck cancer

Diseases of the Esophagus, 2021

Summary Patients with head and neck squamous cell carcinoma (HNSCC) have an increased risk of dev... more Summary Patients with head and neck squamous cell carcinoma (HNSCC) have an increased risk of developing esophageal second primary tumors (ESPTs). We aimed to determine the incidence, stage, and outcome of synchronous ESPTs in patients with HNSCC in a Western population. We performed a prospective, observational, and cohort study. Patients diagnosed with HNSCC in the oropharynx, hypopharynx, any other sub-location in combination with alcohol abuse, or patients with two synchronous HNSCCs, between February 2019 and February 2020 underwent screening esophagogastroduodenoscopy (EGD). ESPT was defined as presence of esophageal squamous cell carcinoma (ESCC) or high grade dysplasia (HGD). Eighty-five patients were included. A lesion suspected for ESPT was detected in 14 of 85 patients, which was pathologically confirmed in five patients (1 ESCC and 4 HGD). The radiotherapy field was extended to the esophagus in two of five patients, HGD was treated with endoscopic resection in three of f...

Research paper thumbnail of Intraoperative Assessment of the Resection Specimen Facilitates Achievement of Adequate Margins in Oral Carcinoma

Frontiers in Oncology, 2020

BackgroundInadequate resection margins in oral cavity squamous cell carcinoma have an adverse eff... more BackgroundInadequate resection margins in oral cavity squamous cell carcinoma have an adverse effect on patient outcome. Intraoperative assessment provides immediate feedback enabling the surgeon to achieve adequate resection margins. The goal of this study was to evaluate the value of specimen-driven intraoperative assessment by comparing the margin status in the period before and the period after the introduction of specimen-driven assessment as a standard of care (period 2010–2012 vs period 2013–2017).MethodsA cohort of patients surgically treated for oral squamous cell carcinoma at the Erasmus MC Cancer Institute, Rotterdam, between 2010–2012 was studied retrospectively and compared to results of a prospectively collected cohort between 2013–2017. The frequency, type and results of intraoperative assessment of resection margins were analyzed.ResultsOne hundred seventy-four patients were included from 2010–2012, 241 patients were included from 2013–2017. An increase in the freque...

Research paper thumbnail of Is the Depth of Invasion a Marker for Elective Neck Dissection in Early Oral Squamous Cell Carcinoma?

Frontiers in Oncology, 2021

ObjectiveThe depth of invasion (DOI) is considered an independent risk factor for occult lymph no... more ObjectiveThe depth of invasion (DOI) is considered an independent risk factor for occult lymph node metastasis in oral cavity squamous cell carcinoma (OCSCC). It is used to decide whether an elective neck dissection (END) is indicated in the case of a clinically negative neck for early stage carcinoma (pT1/pT2). However, there is no consensus on the cut-off value of the DOI for performing an END. The aim of this study was to determine a cut-off value for clinical decision making on END, by assessing the association of the DOI and the risk of occult lymph node metastasis in early OCSCC.MethodsA retrospective cohort study was conducted at the Erasmus MC, University Medical Centre Rotterdam, The Netherlands. Patients surgically treated for pT1/pT2 OCSCC between 2006 and 2012 were included. For all cases, the DOI was measured according to the 8th edition of the American Joint Committee on Cancer guideline. Patient characteristics, tumor characteristics (pTN, differentiation grade, perin...

Research paper thumbnail of The unveiled reality of human papillomavirus as risk factor for oral cavity squamous cell carcinoma

International Journal of Cancer, 2021

The prognostic impact of human papillomavirus (HPV) in oropharyngeal cancer is generally acknowle... more 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 to detect HPV in nonoropharyngeal cancers, the relatively small cohorts studied and consequently the shortfall of convincing data. In our study, we used a validated, nucleic acid‐based workflow to assess HPV‐prevalence in a consecutive cohort of 1016 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 and 2014 at two Dutch university medical centers were included (N = 1069). For...

Research paper thumbnail of Current Intraoperative Imaging Techniques to Improve Surgical Resection of Laryngeal Cancer: A Systematic Review

Cancers, 2021

Laryngeal cancer is a prevalent head and neck malignancy, with poor prognosis and low survival ra... more Laryngeal cancer is a prevalent head and neck malignancy, with poor prognosis and low survival rates for patients with advanced disease. Treatment consists of unimodal therapy through surgery or radiotherapy in early staged tumors, while advanced stage tumors are generally treated with multimodal chemoradiotherapy or (total) laryngectomy followed by radiotherapy. Still, the recurrence rate for advanced laryngeal cancer is between 25 and 50%. In order to improve surgical resection of laryngeal cancer and reduce local recurrence rates, various intraoperative optical imaging techniques have been investigated. In this systematic review, we identify these technologies, evaluating the current state and future directions of optical imaging for this indication. Narrow-band imaging (NBI) and autofluorescence (AF) are established tools for early detection of laryngeal cancer. Nonetheless, their intraoperative utility is limited by an intrinsic inability to image beyond the (sub-)mucosa. Likew...

Research paper thumbnail of Increased risk of second primary tumours in patients with oesophageal squamous cell carcinoma: a nationwide study in a Western population

United European Gastroenterology Journal, 2021

BackgroundPatients with primary oesophageal squamous cell carcinoma are at risk of developing mul... more BackgroundPatients with primary oesophageal squamous cell carcinoma are at risk of developing multiple primary tumours in the upper aero digestive tract. To date, most studies are performed in the Asian population. We aimed to evaluate the risk of multiple primary tumours in the upper aero digestive tract and stomach in patients with oesophageal squamous cell carcinoma in a Western population.MethodsWe performed a nationwide, retrospective cohort study in collaboration with the Netherlands Cancer Registry. Patients with primary oesophageal squamous cell carcinoma, diagnosed between 2000 and 2016, were included. Primary endpoints were synchronous and metachronous multiple primary tumour risk.ResultsThe cohort consisted of 9058 patients, diagnosed with oesophageal squamous cell carcinoma (male: 57.3%, median age 67 years). In 476 patients (5.3%), 545 multiple primary tumours have been diagnosed. Most of them were located in the head and neck region (49.5%). Among all multiple primary ...

Research paper thumbnail of Intraoperative Assessment of Resection Margins in Oral Cavity Cancer: This is the Way

Journal of Visualized Experiments

The goal of head and neck oncological surgery is complete tumor resection with adequate resection... more The goal of head and neck oncological surgery is complete tumor resection with adequate resection margins while preserving acceptable function and appearance. For oral cavity squamous cell carcinoma (OCSCC), different studies showed that only 15%-26% of all resections are adequate. A major reason for the low number of adequate resections is the lack of information during surgery; the margin status is only available after the final histopathologic assessment, days after surgery. The surgeons and pathologists at the Erasmus MC University Medical Center in Rotterdam started the implementation of specimen-driven intraoperative assessment of resection margins (IOARM) in 2013, which became the standard of care in 2015. This method enables the surgeon to turn an inadequate resection into an adequate resection by performing an additional resection during the initial surgery. Intraoperative assessment is supported by a relocation method procedure that allows accurate identification of inadequate margins (found on the specimen) in the wound bed. The implementation of this protocol resulted in an improvement of adequate resections from 15%-40%. However, the specimen-driven IOARM is not widely adopted because grossing fresh tissue is counter-intuitive for pathologists. The fear exists that grossing fresh tissue will deteriorate the anatomical orientation, shape, and size of the specimen and therefore will affect the final histopathologic assessment. These possible negative effects are countered by the described protocol. Here, the protocol for specimen-driven IOARM is presented in detail, as performed at the institute.

Research paper thumbnail of A novel immunohistochemical scoring system reveals associations of C-terminal MET, ectodomain shedding, and loss of E-cadherin with poor prognosis in oral squamous cell carcinoma

Human Pathology, 2020

Take-down policy If you believe that this document breaches copyright please contact us providing... more Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Research paper thumbnail of Absent and abundant MET immunoreactivity is associated with poor prognosis of patients with oral and oropharyngeal squamous cell carcinoma

Oncotarget, 2016

Although the receptor tyrosine kinase (RTK) MET is widely expressed in head and neck squamous cel... more Although the receptor tyrosine kinase (RTK) MET is widely expressed in head and neck squamous cell carcinoma (HNSCC), its prognostic value remains unclear. This might be due to the use of a variety of antibodies and scoring systems. Here, the reliability of five commercial C-terminal MET antibodies (D1C2, CVD13, SP44, C-12 and C-28) was evaluated before examining the prognostic value of MET immunoreactivity in HNSCC. Using cancer cell lines, it was shown that D1C2 and CVD13 specifically detect MET under reducing, native and formalin-fixed paraffin-embedded (FFPE) conditions. Immunohistochemical staining of routinely FFPE oral SCC with D1C2 and CVD13 demonstrated that D1C2 is most sensitive in the detection of membranous MET. Examination of membranous D1C2 immunoreactivity with 179 FFPE oral and oropharyngeal SCC-represented in a tissue microarray-illustrated that staining is either uniform (negative or positive) across tumors or differs between a tumor's center and periphery. Ultimately, statistical analysis revealed that D1C2 uniform staining is significantly associated with poor 5-year overall and disease free survival of patients lacking vasoinvasive growth (HR = 3.019, p < 0.001; HR = 2.559, p < 0.001). These findings might contribute to reliable stratification of patients eligible for treatment with biologicals directed against MET.

Research paper thumbnail of The potential use of big data in oncology

Oral Oncology, 2019

In this era of information technology, big data analysis is entering biomedical sciences. But wha... more In this era of information technology, big data analysis is entering biomedical sciences. But what is big data, where do they come from and what can we do with it? In this commentary, the main sources of big data are explained, especially in (head and neck) oncology. It also touches upon the need to integrate various sources of clinical, pathological and quality-of-life data. It discusses some initiatives in linking of such datasets on a nationwide scale in the Netherlands. Finally, it touches upon important issues regarding governance, FAIRness of data and the need to bring into place the necessary infrastructures needed to fully exploit the full potential of big data sets in head and neck cancer.

Research paper thumbnail of Towards the Optical Detection of Field Cancerization in the Buccal Mucosa of Patients with Lung Cancer

Translational Oncology, 2019

INTRODUCTION: An increase in detection of early-stage asymptomatic lung tumors could increase the... more INTRODUCTION: An increase in detection of early-stage asymptomatic lung tumors could increase the overall survival rate of lung cancer patients. A new approach to cancer (pre-)screening focusses on detecting field cancerization instead of the tumor itself. The objective of this study was to investigate the use of optical spectroscopy to detect field cancerization in the buccal mucosa of lung cancer patients. METHODS: Optical buccal mucosa measurements were performed in lung cancer patients and controls using multidiameter single-fiber reflectance spectroscopy. We analyzed whether the measured optical parameters could distinguish lung cancer patients from controls. RESULTS: Twenty-three lung cancer patients, 24 chronic obstructive pulmonary disease (COPD) control patients, and 36 non-COPD controls were included. The majority of tumors were non-small-cell lung carcinomas (96%) and classified as stage I (48%). The tissue scattering properties m s ' and g at 800 nm and the tissue bilirubin concentration were all near-significantly different (P ¼ .072, 0.058, and 0.060, respectively) between the lung cancer and COPD group. m s ' at 800 nm had a sensitivity of 74% and a specificity of 63%. The microvascular blood oxygen saturation of the lung cancer patients was also higher than the COPD patients (78% vs. 62%, P ¼ .002), this is probably a consequence of the systemic effect of COPD. CONCLUSIONS: We have demonstrated that m s ' at 800 nm is increased in the buccal mucosa of patients with lung cancer compared to controls with COPD. This might be an indication of field cancerization in the oral cavity of patients with lung cancer.

Research paper thumbnail of Relocation of inadequate resection margins in the wound bed during oral cavity oncological surgery: A feasibility study

Head & Neck, 2019

Background: Specimen-driven intraoperative assessment of the resection margins provides immediate... more Background: Specimen-driven intraoperative assessment of the resection margins provides immediate feedback if an additional excision is needed. However, relocation of an inadequate margin in the wound bed has shown to be difficult. The objective of this study is to assess a reliable method for accurate relocation of inadequate tumor resection margins in the wound bed after intraoperative assessment of the specimen. Methods: During oral cavity cancer surgery, the surgeon placed numbered tags on both sides of the resection line in a pair-wise manner. After resection, one tag of each pair remained on the specimen and the other tag in the wound bed. Upon detection of an inadequate margin in the specimen, the tags were used to relocate this margin in the wound bed. Results: The method was applied during 80 resections for oral cavity cancer. In 31 resections an inadequate margin was detected, and based on the paired tagging an accurate additional resection was achieved. Conclusion: Paired tagging facilitates a reliable relocation of inadequate margins, enabling an accurate additional resection during the initial surgery.

Research paper thumbnail of Screening for Head and Neck Second Primary Tumors in Patients with Esophageal Squamous Cell Cancer: A Systematic Review and Meta-Analysis

ESGE Days 2019, 2019

Background: Esophageal squamous cell carcinomas (ESCCs) are often accompanied by head and neck se... more Background: Esophageal squamous cell carcinomas (ESCCs) are often accompanied by head and neck second primary tumors (HNSPTs). The prognosis of patients with an additional HNSPT is worse compared with patients with only ESCC. Therefore, early detection of HNSPTs may improve the overall outcome of patients with ESCC. The purpose of this study was to investigate the yield of endoscopic screening for HNSPTs in patients with primary ESCC. Methods: We conducted a systematic literature search of all available databases. Studies were included if ESCC patients were endoscopically screened for HNSPT. The primary outcome was the pooled prevalence of HNSPTs. Results: Twelve studies, all performed in Japan, were included in this systematic review with a total of 6483 patients. The pooled prevalence of HNSPTs was 6.7% (95% confidence interval: 4.9-8.4). The overall heterogeneity was high across the studies (I 2 ¼ 89.0%, p < 0.001). Most HNSPTs were low stage (85.3%) and located in the hypopharynx (60.3%). The proportion of synchronous (48.2%) and metachronous (51.8%) HNSPTs was comparable. Conclusion: Based on our results, HNSPT screening could be considered in patients with primary ESCC. All studies were performed in Japan; it is therefore not clear whether this consideration applies to the Western world.

Research paper thumbnail of Quality of life and voice outcome of patients treated with transoral CO2 laser microsurgery for early glottic carcinoma (T1–T2): a 2-year follow-up study

European Archives of Oto-Rhino-Laryngology, 2019

Purpose Longitudinal studies in laryngeal cancer can provide clinicians information about short-t... more Purpose Longitudinal studies in laryngeal cancer can provide clinicians information about short-term and long-term functional outcomes, like quality of life (QoL) and voice outcome. This information is important when counseling patients or choosing a primary treatment modality. The present study assessed long-term (2 years) QoL and voice outcome in patients with extended T1 and limited T2 glottic carcinoma treated with transoral CO 2 laser microsurgery (TLM) (unilateral type III or bilateral type II resections). Methods Three questionnaires were administered: the Voice Handicap Index (VHI), the European Organization for Research and Treatment of Cancer (EORTC) QoL questionnaire (QLQ)-C30, the EORTC QLQ-HN35. A perceptual voice evaluation at six different time points was conducted: preoperatively, and postoperatively at 6 weeks, 3 months, 6 months, 1 year, and 2 years. Fluctuations over time were investigated. Results Sixty-one patients were included in the analysis. Patients reported high-level functioning and low symptom scores 2 years postoperatively. Gender significantly affected the VHI scores at 2 years (mean VHI scores: female 8.7 vs. male, 23.9; p = 0.023). The major improvement in VHI scores was observed within the first 6 months. The tumor stage (T1a, T1b, and T2) significantly impacted the grade (mean scores at 2 years: 1.0, 1.9, and 1.7; p = 0.001). These scores stabilized at 6 months. Conclusions Patients show good long-term QoL with low symptom scores, a low voice handicap, and mild to moderate dysphonia, 2 years postoperatively. Scores stabilize at 6 months and provide a clear indication of status at 1 and 2 years.

Research paper thumbnail of A clinicopathological study and prognostic factor analysis of 177 salivary duct carcinoma patients from The Netherlands

International Journal of Cancer, 2018

Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a... more Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a need for better prognostication and novel treatments. The aim of this national cohort study was to investigate clinical outcome, prognostic factors, androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2) expression. SDC patients diagnosed between 1990 and 2014 were identified by the Nationwide Network and Registry of Histo‐ and Cytopathology in the Netherlands (PALGA). Subsequently, medical records were evaluated and pathological diagnoses reviewed. Data were analyzed for overall survival (OS), disease‐free survival (DFS), distant metastasis‐free survival (DMFS) and prognostic factors. AR was evaluated by immunohistochemistry (IHC), HER2 by IHC and fluorescent in‐situ hybridization. A total of 177 patients were included. The median age was 65 years, 75% were male. At diagnosis, 68% presented with lymph node metastases and 6% with distant metastases. Median OS, DFS an...

Research paper thumbnail of Survival of patients with head and neck cancer with metachronous multiple primary tumors is surprisingly favorable

Head & Neck, 2019

Background: The objectives of this study are to determine the incidence and survival rate of pati... more Background: The objectives of this study are to determine the incidence and survival rate of patients with head and neck squamous cell carcinoma (HNSCC) with multiple primary tumors (MPT) in the HN-region, lung, or esophagus. Methods: Patient and tumor specific data of 1372 patients with HNSCC were collected from both the national cancer registry and patient records to ensure highquality double-checked data. Results: The total incidence of MPTs in the HN-region, lung, and esophagus in patients with HNSCC was 11% (149/1372). Patients with lung MPTs and esophageal MPTs had a significant worse 5-year survival than patients with HN-MPTs (29%, 14%, and 67%, respectively, P < 0.001). The 5-year survival rate for synchronous HN MPTs was only 25%, whereas it was surprisingly high for patients with metachronous HN MPT (85%, P < 0.001). Conclusions: One of 10 patients with HNSCC develop MPTs in the HN-region, lung, or esophagus. The 5-year survival of patients with metachronous HN MPTs was surprisingly favorable.