Publications by authors named "Olga Hamming-Vrieze"

45 Publications

Postoperative Radiotherapy in Stage I-III Merkel Cell Carcinoma.

Radiother Oncol 2021 Nov 25. Epub 2021 Nov 25.

Department of medical oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

Background: Postoperative radiotherapy (PORT) is currently recommended for the treatment of Merkel cell carcinoma. Nevertheless, deviations occur frequently due to the generally elderly and frail patient population. We aimed to evaluate the influence of PORT on survival in stage I-III MCC patients treated in the Netherlands.

Methods: Patients were included retrospectively between 2013 and 2018. Fine-Gray method was used for cumulative incidence of recurrence and MCC-related survival, cox regression was performed for overall survival (OS). Analyses were performed in patients with clinical (sentinel node biopsy [SN] not performed) stage I/II (c-I/II-MCC), pathologic (SN negative) stage I/II (p-I/II-MCC) and stage III MCC (III-MCC), separately. Propensity score matching (PSM) was performed to assess confounding by indication.

Results: In total 182 patients were included, 35 had p-I/II-MCC, 69 had c-I/II-MCC and 78 had III-MCC. Median follow up time was 53.5 (IQR 33.4-67.4), 30.5 (13.0-43.6) and 29.3 (19.3-51.0) months, respectively. Multivariable analysis showed PORT to be associated with less recurrences and improved OS, but not with MCC-related survival. In stage III-MCC, extracapsular extension (sub-distribution hazard [SDH] 4.09, p=0.012) and PORT (SDH 0.45, p=0.044) were associated with recurrence, and ≥4 positive lymph nodes (SDH 3.24, p=0.024) were associated with MCC-related survival.

Conclusions: PORT was associated with less recurrences and improved OS in patients with stage I-III MCC, but not with improved MCC-related survival. Trends in OS benefit are likely to be caused by selection bias suggesting further refinement of criteria for PORT is warranted, for instance by taking life expectancy into account.
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http://dx.doi.org/10.1016/j.radonc.2021.11.017DOI Listing
November 2021

Comparisons of normal tissue complication probability models derived from planned and delivered dose for head and neck cancer patients.

Radiother Oncol 2021 11 4;164:209-215. Epub 2021 Oct 4.

Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address:

Background And Purpose: Normal tissue complication probability (NTCP) models are typically derived from the planned dose distribution, which can deviate from the delivered dose due to anatomical day-to-day variations. The aim of this study was to compare NTCP models derived from the planned and the delivered dose for head and neck cancer (HNC) patients.

Material And Method: 322 HNC patients who received radiotherapy with daily CBCT guidance were included in this retrospective study. The delivered dose was estimated by deformably accumulating dose from daily CBCT to planning anatomy. We used a Lyman-Kutcher-Burman NTCP model, to relate the equivalent uniform dose (EUD) of organs at risk (OAR) with oral mucositis, xerostomia and dysphagia respectively. We compared the model parameters and performances.

Results: The median differences between planned and delivered EUD to the OARs were significantly larger for patients with toxicity than without for acute dysphagia (≥G2 and ≥G3) and late dysphagia (≥G3) (p < 0.05). Those differences resulted in small differences in steepness and agreement to the data between delivered- and planned-fitted NTCP curves, and the differences were not significant. The differences in AUC were less than 0.01.

Conclusion: Differences between delivered and planned dose did not lead to significant differences in NTCP curves. The additional clinical relevance of NTCP models using accumulated dose for oral mucositis, xerostomia and dysphagia in HNC radiotherapy is likely to be limited.
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http://dx.doi.org/10.1016/j.radonc.2021.09.015DOI Listing
November 2021

Deterioration of Intended Target Volume Radiation Dose Due to Anatomical Changes in Patients with Head-and-Neck Cancer.

Cancers (Basel) 2021 Aug 24;13(17). Epub 2021 Aug 24.

Department of Radiation Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

Delivered radiation dose can differ from intended dose. This study quantifies dose deterioration in targets, identifies predictive factors, and compares dosimetric to clinical patient selection for adaptive radiotherapy in head-and-neck cancer patients. One hundred and eighty-eight consecutive head-and-neck cancer patients treated up to 70 Gy were analyzed. Daily delivered dose was calculated, accumulated, and compared to the planned dose. Cutoff values (1 Gy/2 Gy) were used to assess plan deterioration in the highest/lowest dose percentile (D/D). Differences in clinical factors between patients with/without dosimetric deterioration were statistically tested. Dosimetric deterioration was evaluated in clinically selected patients for adaptive radiotherapy with CBCT. Respectively, 16% and 4% of patients had deterioration over 1 Gy in D and D in any of the targets, this was 5% (D) and 2% (D) over 2 Gy. Factors associated with deterioration of D were higher baseline weight/BMI, weight gain early in treatment, and smaller PTV margins. The sensitivity of visual patient selection with CBCT was 22% for detection of dosimetric changes over 1 Gy. Large dose deteriorations in targets occur in a minority of patients. Clinical prediction based on patient characteristics or CBCT is challenging and dosimetric selection tools seem warranted to identify patients in need for ART, especially in treatment with small PTV margins.
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http://dx.doi.org/10.3390/cancers13174253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428222PMC
August 2021

Reduction of GTV to high-risk CTV radiation margin in head and neck squamous cell carcinoma significantly reduced acute and late radiation-related toxicity with comparable outcomes.

Radiother Oncol 2021 09 24;162:170-177. Epub 2021 Jul 24.

Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background And Purpose: We aim to retrospectively investigate whether reducing GTV to high-risk CTV margin will significantly reduce acute and late toxicity without jeopardizing outcome in head-and-neck squamous cell carcinoma (HNSCC) treated with definitive (chemo)radiation.

Materials And Methods: Between April 2015 and April 2019, 155 consecutive patients were treated with GTV to high-risk CTV margin of 10 mm and subsequently another 155 patients with 6 mm margin. The CTV-PTV margin was 3 mm for both groups. All patients were treated with volumetric-modulated arc therapy with daily image-guidance using cone-beam CT. End points of the study were acute and late toxicity and oncologic outcomes.

Results: Overall acute grade 3 toxicity was significantly lower in 6 mm, compared to 10 mm group (48% vs. 67%, respectively, p < 0.01). The same was true for acute grade 3 mucositis (18% vs. 34%, p < 0.01) and grade ≥ 2 dysphagia (67% vs. 85%, p < 0.01). Also feeding tube-dependency at the end of treatment (25% vs. 37%, p = 0.02), at 3 months (12% and 25%, p < 0.01), and at 6 months (6% and 15%, p = 0.01) was significantly less in 6 mm group. The incidence of late grade 2 xerostomia was also significantly lower in the 6 mm group (32% vs. 50%, p < 0.01). The 2-year rates of loco-regional control, disease-free and overall survival were 78.7% vs. 73.1%, 70.6% vs. 61.4%, and 83.2% vs. 74.4% (p > 0.05, all).

Conclusion: The first study reporting on reduction of GTV to high-risk CTV margin from 10 to 6 mm showed significant reduction of the incidence and severity of radiation-related toxicity without reducing local-regional control and survival.
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http://dx.doi.org/10.1016/j.radonc.2021.07.016DOI Listing
September 2021

National Protocol for Model-Based Selection for Proton Therapy in Head and Neck Cancer.

Int J Part Ther 2021 25;8(1):354-365. Epub 2021 Jun 25.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

In the Netherlands, the model-based approach is used to identify patients with head and neck cancer who may benefit most from proton therapy in terms of prevention of late radiation-induced side effects in comparison with photon therapy. To this purpose, a National Indication Protocol Proton therapy for Head and Neck Cancer patients (NIPP-HNC) was developed, which has been approved by the health care authorities. When patients qualify according to the guidelines of the NIPP-HNC, proton therapy is fully reimbursed. This article describes the procedures that were followed to develop this NIPP-HNC and provides all necessary information to introduce model-based selection for patients with head and neck cancer into routine clinical practice.
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http://dx.doi.org/10.14338/IJPT-20-00089.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270079PMC
June 2021

Defining High-Quality Integrated Head and Neck Cancer Care Through a Composite Outcome Measure: Textbook Outcome.

Laryngoscope 2022 Jan 3;132(1):78-87. Epub 2021 Jul 3.

Department of Head and Neck Surgery, Antoni van Leeuwenhoek-Netherlands Cancer Institute, Amsterdam, The Netherlands.

Objectives/hypothesis: To further improve the quality of head and neck cancer (HNC) care, we developed a composite measure defined as "textbook outcome" (TO).

Methods: We analyzed a retrospective cohort of patients after curvative-intent primary surgery, radiotherapy (RT), or chemoradiation (CRT) for HNC between 2015 and 2018 at the Netherlands Cancer Institute. TO was defined as 1) the start of treatment within 30 days, 2a) satisfactory pathologic outcomes, without 30-day postoperative complications, for the surgically treated group, and 2b), for RT and CRT patients, no unexpected or prolonged hospitalization and toxicity after the completion of treatment as planned.

Results: In total, 392 patients with HNC were included. An overall TO was achieved in 9.6% of patients after surgery, 20.6% after RT, and 2.2% after CRT. Two indicators (margins >5 mm and start treatment <30 days) reduced TO radically for both groups.

Conclusion: TO can aid the evaluation of the quality of care for HNC patients and guide improvement processes.

Level Of Evidence: 3 Laryngoscope, 132:78-87, 2022.
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http://dx.doi.org/10.1002/lary.29720DOI Listing
January 2022

Non-invasive imaging prediction of tumor hypoxia: A novel developed and externally validated CT and FDG-PET-based radiomic signatures.

Radiother Oncol 2020 12 1;153:97-105. Epub 2020 Nov 1.

The-D-Lab, Dpt of Precision Medicine, GROW - School for Oncology, Maastricht University Medical Centre+, The Netherlands; Department of Radiology and Nuclear Imaging, GROW - school for Oncology, Maastricht University Medical Centre+, The Netherlands.

Background: Tumor hypoxia increases resistance to radiotherapy and systemic therapy. Our aim was to develop and validate a disease-agnostic and disease-specific CT (+FDG-PET) based radiomics hypoxia classification signature.

Material And Methods: A total of 808 patients with imaging data were included: N = 100 training/N = 183 external validation cases for a disease-agnostic CT hypoxia classification signature, N = 76 training/N = 39 validation cases for the H&N CT signature and N = 62 training/N = 36 validation cases for the Lung CT signature. The primary gross tumor volumes (GTV) were manually defined by experts on CT. In order to dichotomize between hypoxic/well-oxygenated tumors a threshold of 20% was used for the [F]-HX4-derived hypoxic fractions (HF). A random forest (RF)-based machine-learning classifier/regressor was trained to classify patients as hypoxia-positive/ negative based on radiomic features.

Results: A 11 feature "disease-agnostic CT model" reached AUC's of respectively 0.78 (95% confidence interval [CI], 0.62-0.94), 0.82 (95% CI, 0.67-0.96) and 0.78 (95% CI, 0.67-0.89) in three external validation datasets. A "disease-agnostic FDG-PET model" reached an AUC of 0.73 (0.95% CI, 0.49-0.97) in validation by combining 5 features. The highest "lung-specific CT model" reached an AUC of 0.80 (0.95% CI, 0.65-0.95) in validation with 4 CT features, while the "H&N-specific CT model" reached an AUC of 0.84 (0.95% CI, 0.64-1.00) in validation with 15 CT features. A tumor volume-alone model was unable to significantly classify patients as hypoxia-positive/ negative. A significant survival split (P = 0.037) was found between CT-classified hypoxia strata in an external H&N cohort (n = 517), while 117 significant hypoxia gene-CT signature feature associations were found in an external lung cohort (n = 80).

Conclusion: The disease-specific radiomics signatures perform better than the disease agnostic ones. By identifying hypoxic patients our signatures have the potential to enrich interventional hypoxia-targeting trials.
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http://dx.doi.org/10.1016/j.radonc.2020.10.016DOI Listing
December 2020

Randomized controlled trial to identify the optimal radiotherapy scheme for palliative treatment of incurable head and neck squamous cell carcinoma.

Radiother Oncol 2020 08 14;149:181-188. Epub 2020 May 14.

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

Background: No randomized controlled trials (RCT) have yet identified the optimal palliative radiotherapy scheme in patients with incurable head and neck squamous cell carcinoma (HNSCC). We conducted RCT to compare two radiation schemes in terms of efficacy, toxicity and quality-of-life (QoL).

Materials And Methods: Patients with locally-advanced HNSCC who were ineligible for radical treatment and those with limited metastatic disease were randomly assigned in 1:1 ratio to arm 1 (36 Gy in 6 fractions, twice a week) or arm 2 (50 Gy in 16 fractions, four times a week).

Results: The trial was discontinued early because of slow accrual (34 patients enrolled). Objective response rates were 38.9% and 57.1% for arm 1 and 2 respectively (p = 0.476). The median time to loco-regional progression was not reached. The loco-regional control rates at 1 year was 57.4% and 69.3% in arm 1 and 2 (p = 0.450, HR = 0.56, 95%CI 0.12-2.58). One-year overall survival was 33.3% and 57.1%, with medians of 35.4 and 59.5 weeks, respectively (p = 0.215, HR = 0.55, 95%CI 0.21-1.43). Acute grade ≥3 toxicity was lower in arm 1 (16.7% versus 57.1%, p = 0.027), with the largest difference in grade 3 mucositis (5.6% versus 42.9%, p = 0.027). However, no significant deterioration in any of the patient-reported QoL-scales was found.

Conclusion: No solid conclusion could be made on this incomplete study which is closed early. Long-course radiotherapy did not show significantly better oncologic outcomes, but was associated with more acute grade 3 mucositis. No meaningful differences in QoL-scores were found. Therefore, the shorter schedule might be carefully advocated. However, this recommendation should be interpreted with great caution because of the inadequate statistical power.
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http://dx.doi.org/10.1016/j.radonc.2020.05.020DOI Listing
August 2020

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

Clin Transl Radiat Oncol 2020 Jul 18;23:9-15. Epub 2020 Apr 18.

The D-Lab, Dpt of Precision Medicine, GROW - School for Oncology, Maastricht University, The Netherlands.

Introduction: The presence of hypoxia in head-and-neck squamous cell carcinoma is a negative prognostic factor. PET imaging with [18F] HX4 can be used to visualize hypoxia, but it is currently unknown how this correlates with prognosis. We investigated the prognostic value of [18F] HX4 PET imaging in patients treated with definitive radio(chemo)therapy (RTx).

Materials And Methods: We analyzed 34 patients included in two prospective clinical trials (NCT01347281, NCT01504815). Static [18F] HX4 PET-CT images were collected, both pre-treatment (median 4 days before start RTx, range 1-16), as well as during RTx (median 13 days after start RTx, range 3-17 days). Static uptake at both time points (n = 33 pretreatment, n = 28 during RTx) and measured changes in hypoxic fraction (HF) and hypoxic volume (HV) (n = 27 with 2 time points) were analyzed. Univariate cox analyses were done for local progression free survival (PFS) and overall survival (OS) at both timepoints. Change in uptake was analyzed by comparing outcome with Kaplan-Meier curves and log-rank test between patients with increased and decreased/stable hypoxia, similarly between patients with and without residual hypoxia (rHV = ratio week 2/baseline HV with cutoff 0.2). Voxelwise Spearman correlation coefficients were calculated between normalized [18F] HX4 PET uptake at baseline and week 2.

Results: Analyses of static images showed no prognostic value for [18F] HX4 uptake. Analysis of dynamic changes showed that both OS and local PFS were significantly shorter (log-rank P < 0.05) in patients with an increase in HV during RTx and OS was significantly shorter in patients with rHV, with no correlation to HPV-status. The voxel-based correlation to evaluate spatial distribution yielded a median Spearman correlation coefficient of 0.45 (range 0.11-0.65).

Conclusion: The change of [18F] HX4 uptake measured on [18F] HX4 PET early during treatment can be considered for implementation in predictive models. With these models patients with a worse prognosis can be selected for treatment intensification.
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http://dx.doi.org/10.1016/j.ctro.2020.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184102PMC
July 2020

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

Sci Rep 2020 03 11;10(1):4542. Epub 2020 Mar 11.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

A major challenge in radiomics is assembling data from multiple centers. Sharing data between hospitals is restricted by legal and ethical regulations. Distributed learning is a technique, enabling training models on multicenter data without data leaving the hospitals ("privacy-preserving" distributed learning). This study tested feasibility of distributed learning of radiomics data for prediction of two year overall survival and HPV status in head and neck cancer (HNC) patients. Pretreatment CT images were collected from 1174 HNC patients in 6 different cohorts. 981 radiomic features were extracted using Z-Rad software implementation. Hierarchical clustering was performed to preselect features. Classification was done using logistic regression. In the validation dataset, the receiver operating characteristics (ROC) were compared between the models trained in the centralized and distributed manner. No difference in ROC was observed with respect to feature selection. The logistic regression coefficients were identical between the methods (absolute difference <10). In comparison of the full workflow (feature selection and classification), no significant difference in ROC was found between centralized and distributed models for both studied endpoints (DeLong p > 0.05). In conclusion, both feature selection and classification are feasible in a distributed manner using radiomics data, which opens new possibility for training more reliable radiomics models.
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http://dx.doi.org/10.1038/s41598-020-61297-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066122PMC
March 2020

Long-term swallowing, trismus, and speech outcomes after combined chemoradiotherapy and preventive rehabilitation for head and neck cancer; 10-year plus update.

Head Neck 2020 08 29;42(8):1907-1918. Epub 2020 Feb 29.

Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: The objective of this study was to explore the 10-year plus outcomes of Intensity Modulated Radiotherapy with concomitant chemotherapy (CRT) combined with preventive swallowing rehabilitation (CRT+) for head and neck cancer (HNC).

Methods: Subjective and objective swallowing, trismus, and speech related outcomes were assessed at 10-year plus after CRT+. Outcomes were compared to previously published 6-year results of the same cohort.

Results: Fourteen of the 22 patients at 6-year follow-up were evaluable. Although objective swallowing-related outcomes showed no deterioration (eg, no feeding tube dependency and no pneumonia), swallowing-related quality of life slightly deteriorated over time. No patients had or perceived trismus. Voice and speech questionnaires showed little problems in daily life. Overall quality of life (QOL) was good.

Conclusions: After CRT with preventive rehabilitation exercises for advanced HNC, swallowing, trismus, and speech related outcomes moderately deteriorated from 6 to 10 years, with an on average good overall QOL after.
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http://dx.doi.org/10.1002/hed.26120DOI Listing
August 2020

Protocolised way to cope with anatomical changes in head & neck cancer during the course of radiotherapy.

Tech Innov Patient Support Radiat Oncol 2019 Dec 16;12:34-40. Epub 2019 Dec 16.

Department of Radiation Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.

Introduction: During a course of radiotherapy for head-and-neck-cancer (HNC), non-rigid anatomical changes can be observed on daily Cone Beam CT (CBCT). To objectify responses to these changes, we use a decision support system (traffic light protocol). Action levels orange and red may lead to re-planning. The purpose of this study was to evaluate how often re-planning was done for non-rigid anatomical changes, which anatomical changes led to re-planning and in which subgroups of patients treatment adaptation was deemed necessary.

Materials And Methods: A consecutive series of 388 HNC patients were retrospectively selected using the digital log of CBCT scans. The logs were analyzed for the number of new plans on an original planning CT scan (O-pCT) or a new pCT scan (N-pCT). Reasons for re-planning were categorized into: target volume increase/decrease, body contour decrease/increase and local shift of target volume. Subgroup analysis was performed to investigate relative differences of re-planning between treatment modalities.

Results: For 33 patients the treatment plan was adapted due to anatomical changes, resulting in 37 new plans in total. Re-planning on a N-pCT with complete re-delineation was done 22 times. In fifteen cases a new plan was created after adjustment of contours on the O-pCT. Main reasons for re-planning were target volume increase, body contour decrease and local shifts of target volume. Most re-planning (23%) was seen in patients treated with chemoradiotherapy.

Conclusion: Visual detection of anatomical changes on CBCT during treatment of HNC, results in re-planning in 1 out of 10 patients.
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http://dx.doi.org/10.1016/j.tipsro.2019.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033784PMC
December 2019

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation.

Front Oncol 2019 10;9:1470. Epub 2020 Jan 10.

Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, Netherlands.

Tumor markers that are related to hypoxia, proliferation, DNA damage repair and stem cell-ness, have a prognostic value in advanced stage HNSCC patients when assessed individually. Here we aimed to evaluate and validate this in a multifactorial context and assess interrelation and the combined role of these biological factors in determining chemo-radiotherapy response in HPV-negative advanced HNSCC. RNA sequencing data of pre-treatment biopsy material from 197 HPV-negative advanced stage HNSCC patients treated with definitive chemoradiotherapy was analyzed. Biological parameter scores were assigned to patient samples using previously generated and described gene expression signatures. Locoregional control rates were used to assess the role of these biological parameters in radiation response and compared to distant metastasis data. Biological factors were ranked according to their clinical impact using bootstrapping methods and multivariate Cox regression analyses that included clinical variables. Multivariate Cox regression analyses comprising all biological variables were used to define their relative role among all factors when combined. Only few biomarker scores correlate with each other, underscoring their independence. The different biological factors do not correlate or cluster, except for the two stem cell markers CD44 and SLC3A2 ( = 0.4, < 0.001) and acute hypoxia prediction scores which correlated with T-cell infiltration score, CD8 T cell abundance and proliferation scores ( = 0.52, 0.56, and 0.6, respectively with < 0.001). Locoregional control association analyses revealed that chronic (Hazard Ratio (HR) = 3.9) and acute hypoxia (HR = 1.9), followed by stem cell-ness (CD44/SLC3A2; HR = 2.2/2.3), were the strongest and most robust determinants of radiation response. Furthermore, multivariable analysis, considering other biological and clinical factors, reveal a significant role for EGFR expression (HR = 2.9, < 0.05) and T-cell infiltration (CD8T-cells: HR = 2.2, < 0.05; CD8T-cells/Treg: HR = 2.6, < 0.01) signatures in locoregional control of chemoradiotherapy-treated HNSCC. Tumor acute and chronic hypoxia, stem cell-ness, and CD8 T-cell parameters are relevant and largely independent biological factors that together contribute to locoregional control. The combined analyses illustrate the additive value of multifactorial analyses and support a role for EGFR expression analysis and immune cell markers in addition to previously validated biomarkers. This external validation underscores the relevance of biological factors in determining chemoradiotherapy outcome in HNSCC.
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http://dx.doi.org/10.3389/fonc.2019.01470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966332PMC
January 2020

FDG-PET/CT improves detection of residual disease and reduces the need for examination under anaesthesia in oropharyngeal cancer patients treated with (chemo-)radiation.

Eur Arch Otorhinolaryngol 2019 May 13;276(5):1447-1455. Epub 2019 Feb 13.

Department of Radiation Oncology, Antoni van Leeuwenhoek - Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Purpose: Early detection of residual disease (RD) after (chemo)radiation for oropharyngeal (OPC) is crucial. Surveillance of neck nodes with FDG-PET/CT has been studied extensively, whereas its value for local RD remains less clear. We aim to evaluate the diagnostic value of post-treatment FDG-PET/CT in detecting local RD and the outcome of patients with local RD.

Methods: A cohort (n = 352) of consecutively treated OPC patients at our institute between 2010 and 2017 was evaluated. Patients that underwent FDG-PET/CT at 3 months post-treatment (n = 94) were classified as having complete (CMR) or partial metabolic response (PMR). PMR was defined as visually detectable metabolic activity above the background of surrounding normal tissues. Primary endpoint was diagnostic accuracy in detecting local RD.

Results: Local RD was seen in 19/352 patients (5%), all of them were HPV negative. The FDG-PET/CT had a sensitivity of 100% (8/8), specificity 85% (73/86), PPV 38% (8/21), NPV 100% (73/73), and accuracy 86%. Patients with local RD had significantly worse OS at 2 years, compared to those without (10 versus 88%, P < 0.001). In multivariable analysis, local RD remained a significant predictive factor for death with a hazard ratio of 11.9 (95% CI 5.8-24.3). The number of patients that underwent PET/CT increased over time (P < 0.001), whereas the number of patients that underwent EUA declined (P = 0.072).

Conclusion: FDG-PET/CT has excellent performance for the detection of RD, with the sensitivity and negative predictive value approaching 100%. Due to these excellent results is examination under anaesthesia today in the vast majority of the PET-negative cases not necessary anymore.
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http://dx.doi.org/10.1007/s00405-019-05340-9DOI Listing
May 2019

Improving decision making in larynx cancer by developing a decision aid: A mixed methods approach.

Laryngoscope 2019 12 21;129(12):2733-2739. Epub 2019 Jan 21.

Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Objective: Patients diagnosed with advanced larynx cancer face a decisional process in which they can choose between radiotherapy, chemoradiotherapy, or a total laryngectomy with adjuvant radiotherapy. Clinicians do not always agree on the best clinical treatment, making the decisional process for patients a complex problem.

Methods: Guided by the International Patient Decision Aid (PDA) Standards, we followed three developmental phases for which we held semi-structured in-depth interviews with patients and physicians, thinking-out-loud sessions, and a study-specific questionnaire. Audio-recorded interviews were verbatim transcribed, thematically coded, and analyzed. Phase 1 consisted of an evaluation of the decisional needs and the regular counseling process; phase 2 tested the comprehensibility and usability of the PDA; and phase 3 beta tested the feasibility of the PDA.

Results: Patients and doctors agreed on the need for development of a PDA. Major revisions were conducted after phase 1 to improve the readability and replace the majority of text with video animations. Patients and physicians considered the PDA to be a major improvement to the current counseling process.

Conclusion: This study describes the development of a comprehensible and easy-to-use online patient decision aid for advanced larynx cancer, which was found satisfactory by patients and physicians (available on www.treatmentchoice.info). The outcome of the interviews underscores the need for better patient counseling. The feasibility and satisfaction among newly diagnosed patients as well as doctors will need to be proven. To this end, we started a multicenter trial evaluating the PDA in clinical practice (ClinicalTrials.gov Identifier: NCT03292341).

Level Of Evidence: NA Laryngoscope, 129:2733-2739, 2019.
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http://dx.doi.org/10.1002/lary.27800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899876PMC
December 2019

Radiation dose to the masseter and medial pterygoid muscle in relation to trismus after chemoradiotherapy for advanced head and neck cancer.

Head Neck 2019 05 16;41(5):1387-1394. Epub 2019 Jan 16.

Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: We studied the relationship between trismus (maximum interincisor opening [MIO] ≤35 mm) and the dose to the ipsilateral masseter muscle (iMM) and ipsilateral medial pterygoid muscle (iMPM).

Methods: Pretreatment and post-treatment measurement of MIO at 13 weeks revealed 17% of trismus cases in 83 patients treated with chemoradiation and intensity-modulated radiation therapy. Logistic regression models were fitted with dose parameters of the iMM and iMPM and baseline MIO (bMIO). A risk classification tree was generated to obtain optimal cut-off values and risk groups.

Results: Dose levels of iMM and iMPM were highly correlated due to proximity. Both iMPM and iMM dose parameters were predictive for trismus, especially mean dose and intermediate dose volume parameters. Adding bMIO, significantly improved Normal Tissue Complication Probability (NTCP) models. Optimal cutoffs were 58 Gy (mean dose iMPM), 22 Gy (mean dose iMM) and 46 mm (bMIO).

Conclusions: Both iMPM and iMM doses, as well as bMIO, are clinically relevant parameters for trismus prediction.
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http://dx.doi.org/10.1002/hed.25573DOI Listing
May 2019

SPECT/CT-guided elective nodal irradiation for head and neck cancer: Estimation of clinical benefits using NTCP models.

Radiother Oncol 2019 01 4;130:18-24. Epub 2018 Aug 4.

Department of Radiation Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam, The Netherlands. Electronic address:

Background And Purpose: The great majority of patients with lateralized head and neck squamous cell carcinoma (HNSCC) treated with radiotherapy routinely undergo bilateral elective nodal irradiation (ENI), even though the incidence of contralateral regional failure after unilateral ENI is low. Excluding the contralateral neck from elective irradiation could reduce radiation-related toxicity and improve quality-of-life. The current study investigated the dosimetric benefits of a novel approach using lymph drainage mapping by SPECT/CT to select patients for unilateral ENI.

Patients And Methods: Forty patients with lateralized cT1-3N0-2bM0 HNSCC underwent lymph drainage mapping. Two radiation plans were made; the real plan with which patients were actually treated (selective SPECT/CT-guided plan irradiating the ipsilateral neck ± any contralateral draining level); and the virtual plan (standard plan according to institutional guidelines, as if the same patient would have been treated bilaterally). Radiation doses to clinically important organs-at-risk were compared between the two plans. We used five normal tissue complication probability (NTCP) models to predict the clinical benefits of this approach.

Results: Median dose reductions to the contralateral parotid gland, contralateral submandibular gland, glottic larynx, supraglottic larynx, constrictor muscle and thyroid gland were 19.2, 27.3, 11.4, 9.7, 12.1 and 18.4 Gy, respectively. Median NTCP reductions for xerostomia, contralateral parotid function, dysphagia, hypothyroidism and laryngeal edema were 20%, 14%, 10%, 20% and 5% respectively.

Conclusions: Selective SPECT/CT-guided ENI results in significant dose reductions to various organs-at-risk and corresponding NTCP values, and will subsequently reduce the incidence and severity of different troublesome radiation-related toxicities and improve quality-of-life.
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http://dx.doi.org/10.1016/j.radonc.2018.07.023DOI Listing
January 2019

The impact of margin reduction on outcome and toxicity in head and neck cancer patients treated with image-guided volumetric modulated arc therapy (VMAT).

Radiother Oncol 2019 01 10;130:25-31. Epub 2018 Jul 10.

Department of Radiation Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address:

Background And Purpose: In recent decades, outcomes of patients with head and neck cancer (HNC) have improved as a result of implementing several strategies, such as chemoradiation. However, these improvements were achieved at the cost of increased toxicity. One way to reduce radiation-related toxicity is by reducing the margins.

Materials And Methods: Between 2013 and 2016, 206 consecutive patients were treated with CTV-PTV margin of 5 mm and subsequently 208 patients with 3 mm margin. This study evaluates the impact of reducing clinical target volume (CTV) to planning target volume (PTV) margin on outcome and toxicity.

Results: All patients were treated with volumetric modulated arc therapy (VMAT) with daily-image guidance using cone-beam CT (CBCT). Overall acute grade 3 toxicity was significantly lower in 3 mm-group, compared to 5 mm-group (53.8% vs. 65%, respectively, p = 0.032). The same was true for acute grade 3 mucositis (30.8% vs. 42.2%, p = 0.008) and for acute grade 3 dysphagia (feeding tube-dependence) (22.1% vs. 33.5%, p = 0.026). The incidence of ongoing feeding tube-dependence after 3 months of radiotherapy was 11.1% and 20.4%, respectively (p = 0.012). The 2-year incidence of late grade ≥2 xerostomia was 15.8% and 19.4% (p = 0.8). The 2-year loco-regional control rates of patients treated in 3 mm and 5 mm-groups were 79.9% and 79.2% (p = 1.0). The figures for disease-free survival were 71.5% and 72.7 (p = 0.6) and for overall survival were 75.2% and 75.1% (p = 0.9).

Conclusion: Reducing the CTV-PTV margin from 5 to 3 mm combined with daily CBCT-guided VMAT reduced the severity, frequency, and duration of radiation-related toxicity without jeopardizing outcome.
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http://dx.doi.org/10.1016/j.radonc.2018.06.032DOI Listing
January 2019

Biological PET-guided adaptive radiotherapy for dose escalation in head and neck cancer: a systematic review.

Q J Nucl Med Mol Imaging 2018 Dec 4;62(4):349-368. Epub 2018 Jun 4.

Department of Radiation Oncology, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, The Netherlands.

Introduction: In recent years, the possibility of adapting radiotherapy to changes in biological tissue parameters has emerged. It is hypothesized that early identification of radio-resistant parts of the tumor during treatment provides the possibility to adjust the radiotherapy plan to improve outcome. The aim of this systematic literature review was to evaluate the current state of the art of biological PET-guided adaptive radiotherapy, focusing on dose escalation to radio-resistant tumor.

Evidence Acquisition: A structured literature search was done to select clinical trials including patients with head and neck cancer of the oral cavity, oropharynx, hypopharynx or larynx, with a PET performed during treatment used to develop biological adaptive radiotherapy by: 1) delineation of sub-volumes suitable for adaptive re-planning; 2) in-silico adaptive treatment planning; or 3) treatment of patients with PET based dose escalated adaptive radiotherapy.

Evidence Synthesis: Nineteen articles were selected, 12 articles analyzing molecular imaging signal during treatment and 7 articles focused on biological adaptive treatment planning, of which two were clinical trials. Studied biological pathways include metabolism (FDG), hypoxia (MISO, FAZA and HX4) and proliferation (FLT).

Conclusions: In the development of biological dose adaptation in radiotherapy for head-neck tumors, many aspects of the procedure remain ambiguous. Patient selection, tracer selection for detection of the radio-resistant sub-volumes, timing of adaptive radiotherapy, workflow and treatment planning aspects are discussed in a clinical context.
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http://dx.doi.org/10.23736/S1824-4785.18.03087-XDOI Listing
December 2018

A predictive model for residual disease after (chemo) radiotherapy in oropharyngeal carcinoma: Combined radiological and clinical evaluation of tumor response.

Clin Transl Radiat Oncol 2017 Oct 4;6:1-6. Epub 2017 Aug 4.

Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background And Purpose: Early detection of Residual disease (RD) is vital for salvage possibilities after (chemo) radiatiotherapy for oropharyngeal carcinoma (OPC). We standardized clinical investigation to test its added value to MRI response evaluation and investigated the benefit of FDG-PET/CT.

Materials And Methods: Radiological response evaluation using Ojiri-score was done for 234 patients with OPC, using MRI 12 weeks after (chemo) radiotherapy between 2010 and 2014. The presence of mucosal lesions and/or major complaints (still completely tube feeding-dependent and/or opiate-dependent because of swallowing problems) was scored as clinical suspicion (CS). Retrospectively, the performance of Ojiri to predict RD was compared to CS and both combined using Pearson Chi-squared. Of the whole group, FDG-PET/CT metabolic response (MR) was available in 50 patients.

Results: Twelve out of 234 patients (5.1%) had RD. Ojiri and CS had excellent negative predictive value (NPV) (98% and 100% respectively). The combination of CS and Ojiri reduced false positives by 32% (38-26 patients) without lowering NPV (98%). No patients with complete MR ( = 39) at the FDG-PET/CT had RD compared to 5 (45%) with partial MR.

Conclusion: For response evaluation in OPC, the combination of CS and Ojiri-score improved the predictive accuracy by reducing false positives compared to them individually. FDG-PET/CT is promising to further reduce false positives.
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http://dx.doi.org/10.1016/j.ctro.2017.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862662PMC
October 2017

Local control in sinonasal malignant melanoma: Comparing conventional to hypofractionated radiotherapy.

Head Neck 2018 Jan 16;40(1):86-93. Epub 2017 Oct 16.

Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: The purpose of this study was to analyze the effect of fractionation schedule on local control in postoperative radiotherapy (RT) for sinonasal malignant melanoma.

Methods: Sixty-three patients who were treated with surgery and postoperative RT in 4 accredited head and neck cancer centers in the Netherlands between 1998 and 2013 were retrospectively studied. Outcomes with conventional fractionation (2-2.4 Gy per fraction; n = 27) were compared to hypofractionation (4-6 Gy per fraction; n = 36). The primary endpoint was local control and the secondary endpoint was toxicity.

Results: Comparable local control rates were found after 2 and 5 years (63% vs 64% and 47% vs 53%; P = .73 for, respectively, conventional fractionation vs hypofractionation). Local recurrences were predominantly present ipsilateral (92%) and within the irradiated volume (88%). Late toxicity grade ≥ 3 was observed in 2 of 63 patients, 1 patient in both groups.

Conclusion: Radiotherapy fractionation schedule did not influence the local control rate or the incidence of late toxicity in patients treated with surgery and RT for sinonasal malignant melanoma in this retrospective analysis. Due to this retrospective nature and the limited number of patients, strong recommendations cannot be made. Expected toxicity, patient convenience, and workload may be taken into account for the choice of fractionation schedule until conclusive evidence becomes available.
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http://dx.doi.org/10.1002/hed.24979DOI Listing
January 2018

Contralateral regional recurrence after elective unilateral neck irradiation in oropharyngeal carcinoma: A literature-based critical review.

Cancer Treat Rev 2017 Sep 21;59:102-108. Epub 2017 Jul 21.

Department of Head and Neck Surgery, Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam, The Netherlands.

Background: The head and neck region has rich regional lymphatic network, with a theoretical risk on contralateral metastasis from oropharyngeal cancer (OPC). There is a long-standing convention to irradiate the great majority of these tumors electively to both sides of the neck to reduce the risk of contralateral regional failure (cRF), but this can induce significant toxicity. We aimed to identify patient groups where elective contralateral irradiation may safely be omitted.

Methods: PubMed and EMBASE were searched for original full-text articles in English with a combination of search terms related to the end points: cRF in OPC primarily treated by radiotherapy only to the ipsilateral neck and identifying predictive factors for increased incidence of cRF. The data from the identified studies were pooled, the incidence of cRF was calculated and the correlation with different predictive factors was investigated.

Results: Eleven full-text articles met the inclusion criteria. In these studies, 1116 patients were treated to the ipsilateral neck alone. The mean incidence of cRF was 2.42% (range 0-5.9%, 95% CI 1.6-3.5%). The incidence of cRF correlated only with T-stage (p=0.008), and involvement of midline (p=0.001). However, the significant correlation with T-stage can be explained by the very low incidence of cRF among T1 (0.77%), and disappeared when the incidence of cRF was compared between T2, T3,and T4 (p=0.344).

Conclusion: The incidence of cRF in patients with OPC is very low, with involvement of midline providing the most significant prognosticator. These results call for trials on unilateral elective irradiation in selected groups.
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http://dx.doi.org/10.1016/j.ctrv.2017.07.004DOI Listing
September 2017

Unknown primary head and neck squamous cell carcinoma in the era of fluorodeoxyglucose-positron emission tomography/CT and intensity-modulated radiotherapy.

Head Neck 2017 07 28;39(7):1382-1391. Epub 2017 Mar 28.

Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: The diagnosis and treatment of head and neck carcinoma of unknown primary (CUP) have changed with the introduction of fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT and intensity-modulated radiotherapy (IMRT), with potential implications for outcome.

Methods: We conducted a retrospective analysis of 80 patients with head and neck CUP who were PET-staged and treated with curative intention using IMRT between 2006 and 2016 in the Netherlands Cancer Institute. Patient, tumor, and treatment demographics were recorded and oncologic outcomes were analyzed.

Results: Local control was 100% in mucosal irradiated patients. Regional control was 90%. Ten patients developed distant metastases, which were associated with N3, extracapsular extension (ECE) and lower neck positive lymph nodes. Overall survival (OS) at 5 years was 62% and disease-specific survival was 78%. ECE, N3 neck, multiple levels of positive lymph nodes, and positive lymph nodes in the lower neck were associated with worse prognosis.

Conclusion: Locoregional outcome of head and neck CUP managed with modern techniques is good. Future research needs to focus on reducing toxicity and patients prone for distant metastasis.
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http://dx.doi.org/10.1002/hed.24762DOI Listing
July 2017

Orthovoltage X-rays for Postoperative Treatment of Resected Basal Cell Carcinoma in the Head and Neck Area.

J Cutan Med Surg 2017 May/Jun;21(3):243-249. Epub 2016 Dec 30.

1 Netherlands Cancer Institute/Antoni Van Leeuwenhoek Hospital, Amsterdam, Netherlands.

Background: Surgery is the golden standard for treating basal cell carcinomas. In case of positive tumor margins or recurrent disease, postoperative adjuvant or salvaging therapy is suggested to achieve good local control.

Objective: To retrospectively report on local control and toxicity of postoperative radiotherapy by means of orthovoltage X-rays for residual or recurrent basal cell carcinoma after surgery in the head and neck area.

Methods: Sixty-six surgically resected residual or recurrent basal cell carcinomas of the head and neck region were irradiated postoperatively by means of orthovoltage X-rays at the Netherlands Cancer Institute between January 2000 and February 2015.

Results: After a median follow-up duration of 30.5 months, only 5 recurrences were reported. The 5-year local control rates at 1, 3, and 5 years were 100%, 87%, and 87%, respectively. The 5-year local control rate was 92% for immediate postoperative radiotherapy of incompletely resected basal cell carcinomas, 90% for recurrences after 1 previously performed excision, and 71% for multiple recurrences, namely, a history of more than 1 excision ( P = .437). Acute toxicity healed spontaneously within 3 months. Late toxicities were mild.

Conclusion: Radiotherapy by means of orthovoltage X-ray is an excellent alternative for re-excision in case of incompletely resected or recurrent basal cell carcinomas that are at risk of serious functional and cosmetic impairments after re-excision, with a 5-year local control rate of 87% and a low toxicity profile.
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http://dx.doi.org/10.1177/1203475416687268DOI Listing
May 2018

Quantitative assessment of Zirconium-89 labeled cetuximab using PET/CT imaging in patients with advanced head and neck cancer: a theragnostic approach.

Oncotarget 2017 Jan;8(3):3870-3880

Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.

Biomarkers predicting treatment response to the monoclonal antibody cetuximab in locally advanced head and neck squamous cell carcinomas (LAHNSCC) are lacking. We hypothesize that tumor accessibility is an important factor in treatment success of the EGFR targeting drug. We quantified uptake of cetuximab labeled with Zirconium-89 (89Zr) using PET/CT imaging.Seventeen patients with stage III-IV LAHNSCC received a loading dose unlabeled cetuximab, followed by 10 mg 54.5±9.6 MBq 89Zr-cetuximab. PET/CT images were acquired either 3 and 6 or 4 and 7 days post-injection. 89Zr-cetuximab uptake was quantified using standardized uptake value (SUV) and tumor-to-background ratio (TBR), and correlated to EGFR immunohistochemistry. TBR was compared between scan days to determine optimal timing.Uptake of 89Zr-cetuximab varied between patients (day 6-7: SUVpeak range 2.5-6.2). TBR increased significantly (49±28%, p < 0.01) between first (1.1±0.3) and second scan (1.7±0.6). Between groups with a low and high EGFR expression a significant difference in SUVmean (2.1 versus 3.0) and SUVpeak (3.2 versus 4.7) was found, however, not in TBR. Data is available at www.cancerdata.org (DOI: 10.17195/candat.2016.11.1).In conclusion, 89Zr-cetuximab PET imaging shows large inter-patient variety in LAHNSCC and provides additional information over FDG-PET and EGFR expression. Validation of the predictive value is recommended with scans acquired 6-7 days post-injection.
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http://dx.doi.org/10.18632/oncotarget.13910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354801PMC
January 2017

Analysis of GTV reduction during radiotherapy for oropharyngeal cancer: Implications for adaptive radiotherapy.

Radiother Oncol 2017 02 18;122(2):224-228. Epub 2016 Nov 18.

Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background And Purpose: Adaptive field size reduction based on gross tumor volume (GTV) shrinkage imposes risk on coverage. Fiducial markers were used as surrogate for behavior of tissue surrounding the GTV edge to assess this risk by evaluating if GTVs during treatment are dissolving or actually shrinking.

Materials And Methods: Eight patients with oropharyngeal tumors treated with chemo-radiation were included. Before treatment, fiducial markers (0.035×0.2cm, n=40) were implanted at the edge of the primary tumor. All patients underwent planning-CT, daily cone beam CT (CBCT) and MRIs (pre-treatment, weeks 3 and 6). Marker displacement on CBCT was compared to local GTV surface displacement on MRIs. Additionally, marker displacement relative to the GTV surfaces during treatment was measured.

Results: GTV surface displacement derived from MRI was larger than derived from fiducial markers (average difference: 0.1cm in week 3). During treatment, the distance between markers and GTV surface on MRI in week 3 increased in 33%>0.3cm and in 10%>0.5cm. The MRI-GTV shrank faster than the surrounding tissue represented by the markers, i.e. adapting to GTV shrinkage may cause under-dosage of microscopic disease.

Conclusions: We showed that adapting to primary tumor GTV shrinkage on MRI mid-treatment is potentially not safe since at least part of the GTV is likely to be dissolving. Adjustment to clear anatomical boundaries, however, may be done safely.
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http://dx.doi.org/10.1016/j.radonc.2016.10.012DOI Listing
February 2017

Head and Neck Margin Reduction With Adaptive Radiation Therapy: Robustness of Treatment Plans Against Anatomy Changes.

Int J Radiat Oncol Biol Phys 2016 11 21;96(3):653-60. Epub 2016 Jul 21.

Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address:

Purpose: We set out to investigate loss of target coverage from anatomy changes in head and neck cancer patients as a function of applied safety margins and to verify a cone beam computed tomography (CBCT)-based adaptive strategy with an average patient anatomy to overcome possible target underdosage.

Methods And Materials: For 19 oropharyngeal cancer patients, volumetric modulated arc therapy treatment plans (2 arcs; simultaneous integrated boost, 70 and 54.25 Gy; 35 fractions) were automatically optimized with uniform clinical target volume (CTV)-to-planning target volume margins of 5, 3, and 0 mm. We applied b-spline CBCT-to-computed tomography (CT) deformable registration to allow recalculation of the dose on modified CT scans (planning CT deformed to daily CBCT following online positioning) and dose accumulation in the planning CT scan. Patients with deviations in primary or elective CTV coverage >2 Gy were identified as candidates for adaptive replanning. For these patients, a single adaptive intervention was simulated with an average anatomy from the first 10 fractions.

Results: Margin reduction from 5 mm to 3 mm to 0 mm generally led to an organ-at-risk (OAR) mean dose (Dmean) sparing of approximately 1 Gy/mm. CTV shrinkage was mainly seen in the elective volumes (up to 10%), likely related to weight loss. Despite online repositioning, substantial systematic errors were present (>3 mm) in lymph node CTV, the parotid glands, and the larynx. Nevertheless, the average increase in OAR dose was small: maximum of 1.2 Gy (parotid glands, Dmean) for all applied margins. Loss of CTV coverage >2 Gy was found in 1, 3, and 7 of 73 CTVs, respectively. Adaptive intervention in 0-mm plans substantially improved coverage: in 5 of 7 CTVs (in 6 patients) to <2 Gy of initially planned.

Conclusions: Volumetric modulated arc therapy head and neck cancer treatment plans with 5-mm margins are robust for anatomy changes and show a modest increase in OAR dose. Margin reduction improves OAR sparing with approximately 1 Gy/mm at the expense of target coverage in a subgroup of patients. Patients at risk of CTV underdosage >2 Gy in 0-mm plans may be identified early in treatment using dose accumulation. A single intervention with an average anatomy derived from CBCT effectively mitigates discrepancies.
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http://dx.doi.org/10.1016/j.ijrobp.2016.07.011DOI Listing
November 2016

Orthovoltage for basal cell carcinoma of the head and neck: Excellent local control and low toxicity profile.

Laryngoscope 2016 08 4;126(8):1796-802. Epub 2016 Feb 4.

Netherlands Cancer Institute, Amsterdam, The Netherlands.

Objectives/hypothesis: Evaluation of treatment results of orthovoltage X-rays for a selection of previously untreated favorable basal cell carcinomas (BCC) in the head and neck area concerning local control, cosmetic and functional outcome, and toxicity profile.

Methods: A consecutive series of patients with primarily treated BCCs who were irradiated by means of orthovoltage X-rays in the Netherlands Cancer Institute in Amsterdam between January 2000 and February 2015 were retrospectively evaluated.

Results: Two hundred fifty-three BCCs in 232 patients were primarily treated with orthovoltage X-rays. The local control rates at 1, 3, and 5 years for this selection of basal cell carcinomas were 98.9%, 97.5%, and 96.3%, respectively. Tumor size was the only significant predictor for local control because BCCs < 20 mm had a significantly higher 5-year local control rate than lesions ≥ 20 mm (96.8% vs. 89.4%, P = 0.041). Acute toxicity healed spontaneously without medical intervention, and late toxicity rates were low. Functional impairments were negligible, and the cosmetic outcome was excellent.

Conclusion: Orthovoltage therapy for well-selected favorable BCCs in the head and neck area resulted in excellent local control rates, a low toxicity profile, and apparently satisfactory functional and cosmetic outcomes. Orthovoltage irradiation is a good alternative for surgery for BCCs with favorable histologic prognosis at locations that are at risk for postoperative functional or cosmetic changes, such as the nose or canthus.

Level Of Evidence: 4. Laryngoscope, 126:1796-1802, 2016.
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http://dx.doi.org/10.1002/lary.25865DOI Listing
August 2016

Geometric changes of parotid glands caused by hydration during chemoradiotherapy.

Radiat Oncol 2015 Dec 1;10:246. Epub 2015 Dec 1.

Department of Radiation Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Background: Plan adaptation during the course of (chemo)radiotherapy of H&N cancer requires repeat CT scanning to capture anatomy changes such as parotid gland shrinkage. Hydration, applied to prevent nephrotoxicity from cisplatin, could temporarily alter the hydrogen balance and hence the captured anatomy. The aim of this study was to determine geometric changes of parotid glands as function of hydration during chemoradiotherapy compared to a control group treated with radiotherapy only.

Methods: This study included an experimental group (n = 19) receiving chemoradiotherapy, and a control group (n = 19) receiving radiotherapy only. Chemoradiotherapy patients received cisplatin with 9 l of saline solution during hydration in the first, fourth and seventh week. The delineations of the parotid glands on the planning CT scan were automatically propagated to Cone Beam CT scans using deformable image registration. Relative volume and position of the parotid glands were determined at the second chemotherapy cycle (week four) and at fraction 35.

Results: When saline solution was administrated, the volume temporarily increased on the first day (7.2 %, p < 0.001), second day (10.8 %, p < 0.001) and third day (7.0 %, p = 0.016). The gland positions shifted lateral, the distance between glands increased on the first day with 1.5 mm (p < 0.001), on the second day 2.2 mm (p < 0.001). At fraction 35, with both groups the mean shrinkage was 24 % ± 11 % (1SD) and the mean medial distance between the parotid glands decreased by 0.47 cm ± 0.27 cm.

Conclusions: Hydration significantly modulates parotid gland geometry. Unless, in the context of adaptive RT, a repeat CT scan is timed during a chemotherapy cycle, these effects are of minor clinical relevance.
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http://dx.doi.org/10.1186/s13014-015-0554-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665881PMC
December 2015

Tumor volume as a prognostic factor for local control and overall survival in advanced larynx cancer.

Laryngoscope 2016 Feb 29;126(2):E60-7. Epub 2015 Aug 29.

Department of Head and Neck Oncology and Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands.

Objectives/hypothesis: Tumor volume has been postulated to be an important prognostic factor for oncological outcome after radiotherapy or chemoradiotherapy. This postulate was retrospectively investigated in a consecutively treated cohort of T3-T4 larynx cancer patients.

Study Design: Retrospective cohort study.

Methods: For 166 patients with T3-T4 larynx cancer (1999-2008), pretreatment computed tomography and magnetic resonance imaging scans were available for tumor volume delineation. Patients were treated with radiotherapy, chemoradiotherapy, or total laryngectomy with postoperative radiotherapy. Both a dedicated head and neck radiologist and the first author determined all tumor volumes. Statistical analysis was by Kaplan-Meier plots and Cox proportional hazard models.

Results: Patients with T3 larynx cancer had significantly smaller tumor volumes than patients with T4 larynx cancer (median = 8.1 cm(3) and 15.8 cm(3), respectively; P < .0001). In the group treated with total laryngectomy and postoperative radiotherapy, no association was found between tumor volume and local or locoregional control or overall survival. In the group treated with radiotherapy, a nonsignificant trend was observed between local control and tumor volume. In the chemoradiotherapy group, however, a significant impact of tumor volume was found on local control (hazard ratio = 1.07; 95% confidence interval = 1.01-1.13; P = .028).

Conclusions: Tumor volume was not significantly associated with local control, locoregional control, or overall survival in the surgically treated group. In the group treated with radiotherapy, there was no statistically significant association, but a trend was observed between local control and tumor volume. Only in patients treated with concurrent chemoradiotherapy was a significant impact of tumor volume on local control found.

Level Of Evidence: 4.
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http://dx.doi.org/10.1002/lary.25567DOI Listing
February 2016
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