Publications by authors named "José Belderbos"

151 Publications

Concurrent Chemoradiation, Adjuvant Durvalumab, and KEAP-1/NRF-2 Mutations: A Happy Marriage?

J Thorac Oncol 2021 Aug;16(8):1242-1243

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

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http://dx.doi.org/10.1016/j.jtho.2021.06.008DOI Listing
August 2021

Delivered dose-effect analysis of radiation induced rib fractures after thoracic SBRT.

Radiother Oncol 2021 Jun 21;162:18-25. Epub 2021 Jun 21.

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

Background And Purpose: Anatomical changes during the stereotactic body radiation therapy (SBRT) of early stage non-small cell lung cancer (NSCLC) may cause the delivered dose to deviate from the planned dose. We investigate if normal tissue complication probability (NTCP) models based on the delivered dose predict radiation-induced rib fractures better than models based on the planned dose.

Material And Methods: 437 NSCLC patients treated to a median dose of 3x18 Gy were included. Delivered dose was estimated by accumulating EQD2-corrected fraction doses after being deformed with daily CBCT-to-planning CT deformable image registration. Dosimetric parameters D (dose to a relative volume x) were extracted for each rib included in the CBCTs field-of-view. An NTCP model was constructed for both planned and delivered dose, optimizing the parameters TD (dose with 50% toxicity risk), m (steepness of the curve) and x, using maximum likelihood estimation. Best NTCP model was determined using Akaike weights (Aw). Differences between the models were tested for significance using the Vuong's test.

Results: Median time to fracture of 110 fractured ribs was 22.5 months. The maximum rib dose, D, best predicted fractures for both planned and delivered dose. The average delivered D was significantly lower than planned (p < 0.001). NTCP model based on the delivered D was the best, with Aw = 0.95. The models were not significantly different.

Conclusion: Delivered maximum dose to the ribs was significantly lower than planned. The NTCP model based on delivered dose improved predictions of radiation-induced rib fractures but did not reach statistical significance.
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http://dx.doi.org/10.1016/j.radonc.2021.06.028DOI Listing
June 2021

Challenges in the target volume definition of lung cancer radiotherapy.

Transl Lung Cancer Res 2021 Apr;10(4):1983-1998

University of Manchester, Manchester Academic Health Centre, The Christie NHS Foundation Trust, Manchester, UK.

Radiotherapy, with or without systemic treatment has an important role in the management of lung cancer. In order to deliver the treatment accurately, the clinician must precisely outline the gross tumour volume (GTV), mostly on computed tomography (CT) images. However, due to the limited contrast between tumour and non-malignant changes in the lung tissue, it can be difficult to distinguish the tumour boundaries on CT images leading to large interobserver variation and differences in interpretation. Therefore the definition of the GTV has often been described as the weakest link in radiotherapy with its inaccuracy potentially leading to missing the tumour or unnecessarily irradiating normal tissue. In this article, we review the various techniques that can be used to reduce delineation uncertainties in lung cancer.
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http://dx.doi.org/10.21037/tlcr-20-627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107734PMC
April 2021

Phase 3 Randomized Trial of Prophylactic Cranial Irradiation With or Without Hippocampus Avoidance in SCLC (NCT01780675).

J Thorac Oncol 2021 05 2;16(5):840-849. Epub 2021 Feb 2.

Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Introduction: To compare neurocognitive functioning in patients with SCLC who received prophylactic cranial irradiation (PCI) with or without hippocampus avoidance (HA).

Methods: In a multicenter, randomized phase 3 trial (NCT01780675), patients with SCLC were randomized to standard PCI or HA-PCI of 25 Gy in 10 fractions. Neuropsychological tests were performed at baseline and 4, 8, 12, 18, and 24 months after PCI. The primary end point was total recall on the Hopkins Verbal Learning Test-Revised at 4 months; a decline of at least five points from baseline was considered a failure. Secondary end points included other cognitive outcomes, evaluation of the incidence, location of brain metastases, and overall survival.

Results: From April 2013 to March 2018, a total of 168 patients were randomized. The median follow-up time was 26.6 months. In both treatment arms, 70% of the patients had limited disease and baseline characteristics were well balanced. Decline on the Hopkins Verbal Learning Test-Revised total recall score at 4 months was not significantly different between the arms: 29% of patients on PCI and 28% of patients on HA-PCI dropped greater than or equal to five points (p = 1.000). Performance on other cognitive tests measuring memory, executive function, attention, motor function, and processing speed did not change significantly different over time between the groups. The overall survival was not significantly different (p = 0.43). The cumulative incidence of brain metastases at 2 years was 20% (95% confidence interval: 12%-29%) for the PCI arm and 16% (95% confidence interval: 7%-24%) for the HA-PCI arm.

Conclusions: This randomized phase 3 trial did not find a lower probability of cognitive decline in patients with SCLC receiving HA-PCI compared with conventional PCI. No increase in brain metastases at 2 years was observed in the HA-PCI arm.
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http://dx.doi.org/10.1016/j.jtho.2020.12.024DOI Listing
May 2021

Long-Term Results of Dose-Intensified Fractionated Stereotactic Body Radiation Therapy (SBRT) for Painful Spinal Metastases.

Int J Radiat Oncol Biol Phys 2021 Jun 4;110(2):348-357. Epub 2021 Jan 4.

Department of Radiation Oncology, University Hospital Wuerzburg, Wuerzburg, Germany.

Purpose: To report long-term outcome of fractionated stereotactic body radiation therapy (SBRT) for painful spinal metastases.

Methods And Materials: This prospective, single-arm, multicenter phase 2 clinical trial enrolled 57 patients with 63 painful, unirradiated spinal metastases between March 2012 and July 2015. Patients were treated with 48.5 Gy in 10 SBRT fractions (long life expectancy [Mizumoto score ≤4]) or 35 Gy in 5 SBRT fractions (intermediate life expectancy [Mizumoto score 5-9]). Pain response was defined as pain improvement of a minimum of 2 points on a visual analog scale, and net pain relief was defined as the sum of time with pain response (complete and partial) divided by the overall follow-up time.

Results: All 57 patients received treatment per protocol; 32 and 25 patients were treated with 10- and 5-fraction SBRT, respectively. The median follow-up of living patients was 60 months (range, 33-74 months). Of evaluable patients, 82% had complete or partial pain response (responders) at 3 months' follow-up (primary endpoint), and pain response remained stable over 5 years. Net pain relief was 74% (95% CI, 65%-80%). Overall survival rates of 1, 3, and 5 years were 59.6% (95% CI, 47%-72%), 33.3% (95% CI, 21%-46%), and 21% (95% CI, 10%-32%), respectively. Freedom from local spinal-metastasis progression was 82% at the last imaging follow-up. Late grade-3 toxicity was limited to pain in 2 patients (nonresponders). There were no cases of myelopathy. SBRT resulted in long-term improvements of all dimensions of the 5-level EuroQol 5-Dimension Questionnaire except anxiety/depression.

Conclusions: Fractionated SBRT achieved durable pain response and improved quality of life at minimum late toxicity.
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http://dx.doi.org/10.1016/j.ijrobp.2020.12.045DOI Listing
June 2021

Role of radiotherapy in the management of brain metastases of NSCLC - Decision criteria in clinical routine.

Radiother Oncol 2021 01 11;154:269-273. Epub 2020 Nov 11.

Department of Radiation Oncology, Kantonsspital St. Gallen, Switzerland; Department of Radiation Oncology, University of Bern, Switzerland.

Background: Whole brain radiotherapy (WBRT) is a common treatment option for brain metastases secondary to non-small cell lung cancer (NSCLC). Data from the QUARTZ trial suggest that WBRT can be omitted in selected patients and treated with optimal supportive care alone. Nevertheless, WBRT is still widely used to treat brain metastases secondary to NSCLC. We analysed decision criteria influencing the selection for WBRT among European radiation oncology experts.

Methods: Twenty-two European radiation oncology experts in lung cancer as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) for previous projects and by the Advisory Committee on Radiation Oncology Practice (ACROP) for lung cancer were asked to describe their strategies in the management of brain metastases of NSCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies.

Results: Eight decision criteria (suitability for SRS, performance status, symptoms, eligibility for targeted therapy, extra-cranial tumour control, age, prognostic scores and "Zugzwang" (the compulsion to treat)) were identified. WBRT was recommended by a majority of the European experts for symptomatic patients not suitable for radiosurgery or fractionated stereotactic radiotherapy. There was also a tendency to use WBRT in the ALK/EGFR/ROS1 negative NSCLC setting.

Conclusion: Despite the results of the QUARTZ trial WBRT is still widely used among European radiation oncology experts.
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http://dx.doi.org/10.1016/j.radonc.2020.10.043DOI Listing
January 2021

Dutch translation and linguistic validation of the U.S. National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™).

J Patient Rep Outcomes 2020 Oct 6;4(1):81. Epub 2020 Oct 6.

Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Background: The U.S. National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) is a library of items for assessing symptomatic adverse events by patient self-report in oncology trials. The aim of this multi-site study was to generate and linguistically validate a Dutch language version of the U.S. PRO-CTCAE for use in the Netherlands and Dutch-speaking Belgium.

Methods: All 124 items in the PRO-CTCAE item library were translated into Dutch using established translation procedures, including dual forward translations, reconciliation, back-translation, reconciliation of the source with the back-translation, and expert reviews. Harmonization of the translation for use in both the Netherlands and Belgium was achieved via an iterative review process in which the translations were discussed and reconciled by consensus of PRO experts, clinicians and bilingual Dutch translators. The translated PRO-CTCAE™ items were completed by a geographically-diverse sample of Dutch speaking patients from the Netherlands (n = 40) and Belgium (n = 60), and who were currently receiving or who had recently completed cancer-directed therapy. Patients were diverse with respect to age, sex, educational attainment, and cancer diagnosis. Cognitive debriefing, using a semi-structured interview guide, probed for comprehension and clarity of PRO-CTCAE symptom terms, attributes (e.g. frequency, severity, interference), response choices, and understanding of 'at its worst' and 'in the last 7 days'. Items for which the patient data indicated possible difficulties were considered for revision.

Results: Three items underwent minor phrasing revision and retesting was not deemed necessary. The symptom term for stretch marks was poorly understood by 12.5% of participants, and this item was revised to include parenthetical phrasing. It was retested with 10 participants from Belgium (n = 5) and the Netherlands (n = 5) and demonstrated acceptable comprehension.

Conclusions: The Dutch language version of PRO-CTCAE has been successfully developed and linguistically validated for use in oncology studies in the Netherlands and Dutch-speaking Belgium. Extending the availability of NCI PRO-CTCAE in languages beyond English increases international consistency in the capture of Patient-Reported outcomes in patients participating in cancer clinical trials.
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http://dx.doi.org/10.1186/s41687-020-00249-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538479PMC
October 2020

Hippocampal Avoidance and Memantine for Whole-Brain Radiotherapy: Long-Term Follow-Up Warranted.

J Clin Oncol 2020 10 12;38(29):3454-3455. Epub 2020 Aug 12.

Nicolaus Andratschke, MD, Department of Radiation Oncology, University Hospital and University of Zurich, Zurich, Switzerland; José Belderbos, MD, PhD, Department of Radiation Oncology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; Michael Mayinger, MD, Department of Radiation Oncology, University Hospital and University of Zurich, Zurich, Switzerland; Sanne B. Schagen, PhD, Division of Psychosocial Research and Epidemiology, the Netherlands Cancer Institute, Amsterdam, The Netherlands; and Dirk De Ruysscher, MD, PhD, Department of Radiotherapy (Maastro), Maastricht University Medical Center, GROW Research Institute, Maastricht, the Netherlands.

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http://dx.doi.org/10.1200/JCO.20.00747DOI Listing
October 2020

ESTRO ACROP guidelines for target volume definition in the thoracic radiation treatment of small cell lung cancer.

Radiother Oncol 2020 11 13;152:89-95. Epub 2020 Jul 13.

Department of Radiation Oncology, Kliniken Maria Hilf, Moenchengladbach, Germany; Department of Radiation Oncology, University Hospital Freiburg, Germany.

Radiotherapy (RT) plays a major role in the treatment of small cell lung cancer (SCLC). Therefore, the ACROP committee was asked by ESTRO to provide recommendations on target volume delineation for standard clinical scenarios in definitive (chemo)-radiotherapy (CRT), adjuvant RT for stages I-III SCLC and consolidation thoracic RT for stage IV disease. The aim of these guidelines is to standardise and optimise the process of RT treatment planning for clinical practice and prospective studies. The process for the development of the guidelines included the evaluation of a structured questionnaire followed by a consensus discussion, voting and writing process within the committee. Firstly, we provide recommendations for both the imaging to be performed as part of the diagnostic work-up and for the RT planning process. Secondly, recommendations are made for target volume delineation including delineation of the primary gross tumour volume (GTV) and lymph node GTV and clinical tumour volume (CTV) expansion in the context of definitive and adjuvant RT. With regard to internal target volume (ITV) and planning target volume (PTV) definitions, we make recommendations about the management of geometric uncertainties and target motion. Finally, we provide our opinions on organ at risk (OAR) delineation and organisational issues to be considered.
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http://dx.doi.org/10.1016/j.radonc.2020.07.012DOI Listing
November 2020

Once daily versus twice-daily radiotherapy in the management of limited disease small cell lung cancer - Decision criteria in routine practise.

Radiother Oncol 2020 09 22;150:26-29. Epub 2020 May 22.

Department of Radiation Oncology, Kantonsspital St. Gallen, Switzerland; Department of Radiation Oncology, University of Bern, Switzerland.

Background: In limited disease small cell lung cancer (LD-SCLC), the CONVERT trial has not demonstrated superiority of once-daily (QD) radiotherapy (66 Gy) over twice-daily (BID) radiotherapy (45 Gy). We explored the factors influencing the selection between QD and BID regimens.

Methods: Thirteen experienced European thoracic radiation oncologists as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) were asked to describe their strategies in the management of LD-SCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies.

Results: Logistic reasons, patients' performance status and radiotherapy dose constraints were the three major decision criteria used by most experts in decision making. The use of QD and BID regimens was balanced among European experts, but there was a trend towards the BID regimen for fit patients able to travel twice a day to the radiotherapy site.

Conclusion: BID and QD radiotherapy are both accepted regimens among experts and the decision is influenced by pragmatic factors such as availability of transportation.
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http://dx.doi.org/10.1016/j.radonc.2020.05.004DOI Listing
September 2020

Results of neoadjuvant chemo(radio)therapy and resection for stage IIIA non-small cell lung cancer in The Netherlands.

Acta Oncol 2020 Jul 29;59(7):748-752. Epub 2020 Apr 29.

Department of Surgery, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

Concurrent chemoradiotherapy remains the main treatment strategy for patients with stage IIIA non-small cell lung cancer (NSCLC); stage cT3N1 or cT4N0-1 may be eligible for surgery and potentially resectable stage IIIA (N2) NSCLC for neoadjuvant therapy followed by resection. We evaluated treatment patterns and outcomes of patients with stage IIIA NSCLC in The Netherlands. Primary treatment data of patients with clinically staged IIIA NSCLC between 2010 and 2016 were extracted from The Netherlands Cancer Registry. Patient characteristics were tabulated and 5-year overall survival (OS) was calculated and reported. In total, 9,591 patients were diagnosed with stage IIIA NSCLC. Of these patients, 41.3% were treated with chemoradiotherapy, 11.6% by upfront surgery and 428 patients (4.5%) received neoadjuvant treatment followed by resection. The 5-year OS was 26% after chemoradiotherapy, 40% after upfront surgery and 54% after neoadjuvant treatment followed by resection. Clinical over staging was seen in 42.3% of the patients that were operated without neoadjuvant therapy. In The Netherlands, between 2010 and 2016, 4.5% of patients with stage IIIA NSCLC were selected for treatment with neoadjuvant therapy followed by resection. The 5-year OS in these patients exceeded 50%. However, the outcome might be overestimated due to clinical over staging.
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http://dx.doi.org/10.1080/0284186X.2020.1757150DOI Listing
July 2020

In response to Park, et al.

Radiother Oncol 2020 06 4;147:245-246. Epub 2020 Apr 4.

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

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http://dx.doi.org/10.1016/j.radonc.2020.03.036DOI Listing
June 2020

Correlating Dose Variables with Local Tumor Control in Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer: A Modeling Study on 1500 Individual Treatments.

Int J Radiat Oncol Biol Phys 2020 07 15;107(3):579-586. Epub 2020 Mar 15.

Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland.

Background: Large variation regarding prescription and dose inhomogeneity exists in stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer. The aim of this modeling study was to identify which dose metric correlates best with local tumor control probability to make recommendations regarding SBRT prescription.

Methods And Materials: We combined 2 retrospective databases of patients with non-small cell lung cancer, yielding 1500 SBRT treatments for analysis. Three dose parameters were converted to biologically effective doses (BEDs): (1) the (near-minimum) dose prescribed to the planning target volume (PTV) periphery (yielding BED); (2) the (near-maximum) dose absorbed by 1% of the PTV (yielding BED); and (3) the average between near-minimum and near-maximum doses (yielding BED). These BED parameters were then correlated to the risk of local recurrence through Cox regression. Furthermore, BED-based prediction of local recurrence was attempted by logistic regression and fast and frugal trees. Models were compared using the Akaike information criterion.

Results: There were 1500 treatments in 1434 patients; 117 tumors recurred locally. Actuarial local control rates at 12 and 36 months were 96.8% (95% confidence interval, 95.8%-97.8%) and 89.0% (87.0%-91.1%), respectively. In univariable Cox regression, BED was the best predictor of risk of local recurrence, and a model based on BED had substantially less evidential support. In univariable logistic regression, the model based on BED also performed best. Multivariable classification using fast and frugal trees revealed BED to be the most important predictor, followed by BED.

Conclusions: BED was generally better correlated with tumor control probability than either BED or BED. Because the average between near-minimum and near-maximum doses was highly correlated to the mean gross tumor volume dose, the latter may be used as a prescription target. More emphasis could be placed on achieving sufficiently high mean doses within the gross tumor volume rather than the PTV covering dose, a concept needing further validation.
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http://dx.doi.org/10.1016/j.ijrobp.2020.03.005DOI Listing
July 2020

The use of real-world evidence to audit normal tissue complication probability models for acute esophageal toxicity in non-small cell lung cancer patients.

Radiother Oncol 2020 May 27;146:52-57. Epub 2020 Feb 27.

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

Introduction: The aim of this work is to assess the validity of real world data (RWD) derived from an electronic toxicity registration (ETR). As a showcase, the NTCP-models of acute esophageal toxicity (AET) for concurrent chemoradiation (CCRT) for NSCLC patients were used to validate the ETR of AET before/after dose de-escalation to the mediastinal lymph nodes.

Material And Methods: One hundred and one patients received 24 × 2.75 Gy and 116 patients received de-escalated dose of 24 × 2.42 Gy to the mediastinal lymph nodes. The validity and completeness of the ETR was analyzed. The grade ≥2 AET probability was defined according the V50 Gy and V60 Gy NTCP-models from literature. Validity of the models was assessed by calibration and discrimination. Furthermore, sensitivity and specificity for different cut-off points were determined.

Results: The compliance of ETR was 73-80%, with sensitivity and specificity rates of 83% and 86% for grade ≥2 AET, respectively. Discrimination of both NTCP-models demonstrated a moderate accuracy (V50 model, AUC 0.71; V60-model, AUC 0.69). Dose de-escalation did not influence the accuracy of the V50-model; AUC before: 0.69, and AUC after: 0.71. For the V60-model the model-accuracy decreased after dose de-escalation; AUC before: 0.72 and AUC after: 0.62, respectively.

Conclusion: RWD is a useful method to audit NTCP models in clinical practice. The NTCP models to predict AET in NSCLC patients showed moderate predictive accuracy. For clinical practice, the V50Gy seems to be most stable for dose de-escalation without compromising safety and efficacy.
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http://dx.doi.org/10.1016/j.radonc.2020.02.006DOI Listing
May 2020

The prognostic value of volumetric changes of the primary tumor measured on Cone Beam-CT during radiotherapy for concurrent chemoradiation in NSCLC patients.

Radiother Oncol 2020 05 27;146:44-51. Epub 2020 Feb 27.

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

Introduction: The aim of this study was to identify subgroups of locally advanced NSCLC patients with a distinct treatment response during concurrent chemoradiotherapy (CCRT). Subsequently, we investigated the association of subgroup membership with treatment outcomes.

Methods: 394 NSCLC-patients treated with CCRT between 2007 and 2013 were included. Gross Tumor Volume (GTV) during treatment was determined and relative GTV-volume change from the planning-CT was subsequently calculated. Latent Class Mixed Modeling (LCMM) was used to identify subgroups with distinct volume changes during CCRT. The association of subgroup membership with overall survival (OS), progression free survival (PFS) and local regional control (LRC) was assessed using cox regression analyses.

Results: Three subgroups of GTV-volume change during treatment were identified, with each subsequent subgroup showing a more profound reduction of GTV during treatment. No associations between subgroup membership and OS, PFS nor LRC were observed. Nonetheless, baseline GTV (HR1.42; 95%CI 1.06-1.91) was significantly associated with OS.

Conclusions: Three different subgroups of GTV-volume change during treatment were identified. Surprisingly, these subgroups did not differ in their risk of treatment outcomes. Only patients with a larger GTV at baseline had a significantly worse OS. Therefore, risk stratification at baseline might already be accurate in identifying the best treatment strategy for most patients.
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http://dx.doi.org/10.1016/j.radonc.2020.02.002DOI Listing
May 2020

The role of postoperative thoracic radiotherapy and prophylactic cranial irradiation in early stage small cell lung cancer: Patient selection among ESTRO experts.

Radiother Oncol 2020 04 27;145:45-48. Epub 2019 Dec 27.

Division of Cancer Sciences, University of Manchester & The Christie NHS Foundation Trust Manchester, UK.

Background: The role of prophylactic cranial irradiation (PCI) and thoracic radiotherapy (TRT) is unclear in resected small cell lung cancer (SCLC).

Methods: Thirteen European radiotherapy experts on SCLC were asked to describe their strategies on PCI and TRT for patients with resected SCLC. The treatment strategies were converted into decision trees and analyzed for consensus and discrepancies.

Results: For patients with resected SCLC and positive lymph nodes most experts recommend prophylactic cranial irradiation and thoracic radiotherapy. For elderly patients with resected node negative SCLC, most experts do not recommend thoracic radiotherapy or prophylactic cranial irradiation.

Conclusion: PCI and TRT are considered in patients with resected SCLC and these treatments should be discussed with the patient in the context of shared decision-making.
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http://dx.doi.org/10.1016/j.radonc.2019.11.022DOI Listing
April 2020

Stereotactic Image Guided Lung Radiation Therapy for Clinical Early Stage Non-Small Cell Lung Cancer: A Long-Term Report From a Multi-Institutional Database of Patients Treated With or Without a Pathologic Diagnosis.

Pract Radiat Oncol 2020 Jul - Aug;10(4):e227-e237. Epub 2019 Dec 11.

Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania.

Purpose: Early stage lung cancer is treated with stereotactic body radiation therapy (SBRT) in patients who are unable or unwilling to undergo surgical resection. Some patients' comorbidities are so severe that they are unable to even undergo a biopsy. A clinical diagnosis without biopsy before SBRT has been used, but there are limited data on its efficacy.

Methods And Materials: Data on patients treated with SBRT for non-small cell lung cancer, with and without tissue confirmation, were collected from multiple institutions across Europe, Canada, and the United States. Patients with a minimum of 2 years of comprehensive follow up were selected for analysis. Treatment and patient characteristics were compared. Overall survival (OS), disease-free survival (DFS), cause-specific survival (CSS), and rates of local recurrence (LR), regional recurrence (RR), and distant metastasis (DM) were calculated and analyzed.

Results: A total of 701 patients were identified, of which 67% had tissue confirmation of their tumors. The 3- and 5-year outcomes for OS, CSS, and DFS were 83.8%, 93.1%, 69%, and 60.6%, 86.7%, 45.5%, respectively. The rates for LR, RR, and DM at 3 and 5 years were 6.4%, 9.3%, 14.3%, and 10.5%, 14.3%, 19.7%, respectively. There were no statistically significant differences in survival outcomes or recurrences between the biopsy and no-biopsy cohorts.

Conclusions: SBRT for clinically diagnosed lung cancers is efficacious in appropriately selected patients, with similar outcomes as those with a pathologic diagnosis. Thorough clinical and radiographic evaluations in a multidisciplinary setting are critical to the management of these patients.
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http://dx.doi.org/10.1016/j.prro.2019.12.003DOI Listing
March 2021

Local and regional treatment response by FDG-PET-CT-scans 4 weeks after concurrent hypofractionated chemoradiotherapy in locally advanced NSCLC.

Radiother Oncol 2020 02 22;143:30-36. Epub 2019 Nov 22.

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

Background And Purpose: To investigate associations of early post-treatment Fluorodeoxyglucose-positron-emission-tomography (FDG-PET)-scans with local (LF), regional (RF), distant failure (DF) and overall survival (OS) in locally advanced non-small cell lung cancer (LA-NSCLC)-patients treated with concurrent chemoradiotherapy.

Materials And Methods: Forty-seven stage IIIA-B NSCLC-patients included in a randomized phase II-trial (NTR2230) received 66 Gy (24x2.75 Gy) with low dose Cisplatin +/- Cetuximab. FDG-PET-scans were performed at baseline and 4 weeks post-treatment (range, 1.6-10.1). SUV, SUV, metabolic tumor volume (MTV), total lesion glycolysis (TLG) and gross tumor volume were calculated separately for the primary tumor and the involved lymph nodes to generate baseline, post-treatment, and relative response metrics defined as (metric-metric)/metric. Univariable cox regression analyses were performed to investigate associations between PET-metrics and outcomes.

Results: Metrics resulted from the post-treatment scan and relative response were associated with outcome, but baseline metrics were not. Primary tumor metrics were stronger associated with all outcomes than lymph node metrics. Both the volumetric (TLG/MTV) and intensity (SUV/SUV) PET-metrics were associated with OS. The intensity metrics were associated with LF, while the volumetric PET-metrics were associated with RF/DF. This was in contrast to the nodal metrics, demonstrating only an association between RF and the relative response of TLG/MTV. No preference was found between PET volumetric and intensity metrics associated with outcome.

Conclusion: Early post-treatment PET-metrics are associated with treatment outcome in LA-NSCLC patients treated with chemoradiotherapy. Both volumetric and intensity PET-metrics are useful, but more for the primary tumor than for lymph nodes.
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http://dx.doi.org/10.1016/j.radonc.2019.10.008DOI Listing
February 2020

Risk factors for vertebral compression fracture after spine stereotactic body radiation therapy: Long-term results of a prospective phase 2 study.

Radiother Oncol 2019 12 13;141:62-66. Epub 2019 Sep 13.

Department of Radiation Oncology, University Hospital Wuerzburg, Germany; Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Switzerland.

Purpose: To identify frequency, clinical relevance and risk factors for vertebral compression fracture (VCF) after spine stereotactic body radiation therapy (SBRT) with long-term follow up (FU).

Methods: From 2012 to 2015, 61 lesions (56 patients) were treated within a prospective multicenter phase 2 study (NCT01594892) of SBRT for painful vertebral metastases. Post-SBRT VCF were identified. Anatomical segments, normal and tumor tissue of treated vertebrae were segmented for volumetric analyses. Predictive factors for VCF were identified by logistic regression.

Results: Median clinical and radiological FU for all patients was 16.2 months (range, 0-68.2) and 7.8 months (range, 0-66.9), respectively. Local metastasis control was observed in 82% of lesions at last imaging FU. Post-SBRT VCF occurred in 21 lesions (34.4%): 16.4% showed a progressive VCF, while a new VCF occurred in 18.0%. 3/56 (5.4%) patients developed painful VCF defined as pain increase by ≥2 on the visual analogue scale (VAS) and 2 (3.6%) patients required surgical stabilization. Pre-SBRT VCF, localization in the thoracic spine, Bilsky score >0, SINS score, pre-SBRT osteolytic volume and metastatic vertebral body (VB) involvement were predictive factors for VCF on univariate analysis. Relative VB involvement, osteolytic volume and pre-SBRT VCF remained in the multivariate logistic regression model that had AUC = 0.930, 83.3% sensitivity and 96.6% specificity.

Conclusion: Spine SBRT resulted in favorable long-term pain and local metastasis control. Despite post-SBRT VCF being observed after one third of treatments, this was symptomatic in only 5% of patients. Predictive factors for developing VCF were identified which could contribute to better selection of patients for spine SBRT.
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http://dx.doi.org/10.1016/j.radonc.2019.08.026DOI Listing
December 2019

Safety and efficacy of reduced dose and margins to involved lymph node metastases in locally advanced NSCLC patients.

Radiother Oncol 2020 02 17;143:66-72. Epub 2019 Aug 17.

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

Background And Purpose: (Chemo)Radiotherapy for locally advanced non-small lung cancer (LA-NSCLC) causes severe dysphagia due to the radiation dose to the mediastinal lymphadenopathy. Reducing the dose to the mediastinum and the margins to the planning target volume (PTV) might reduce severe toxicity rates. The results of both adaptations in LA-NSCLC patients receiving (chemo)radiotherapy were analysed.

Materials And Methods: 308 LA-NSCLC patients were included in an observational study. Both cohorts received hypofractionated RT (24 × 2.75 Gy) of 70 Gy (EQD2) to the primary tumour. The reference-cohort (N = 170) received the same dose of 70 Gy (EQD2) to the involved lymph nodes, while the reduction-cohort (N = 138) received 24 × 2.42 Gy, biologically equivalent to 60 Gy (EQD2). Furthermore, the patient-specific PTV-margins for both the primary tumour and lymph nodes were reduced by 2-3 mm in the reduction-cohort after implementing a carina based correction strategy. The effects on toxicity, regional failure and overall survival (OS) were assessed.

Results: The acute grade 3 (G3) dysphagia and G3 pulmonary toxicity decreased significantly from 12.9% to 3.6% and 4.1% versus 0%, respectively. The regional failures were comparable: 5.9% versus 4.3% (p = 0.546). The median OS was significantly different: 26 months (reference-cohort) versus 35 months (reduction-cohort). After correction for confounders, the association between the reduction-cohort and OS remained significant (HR 0.63 versus HR 0.70).

Conclusion: A reduction in PTV-margins and dose from 70 Gy to 60 Gy to the involved lymph nodes in LA-NSCLC patients receiving (chemo)radiotherapy did not result in an increase in regional failures. Moreover, significantly lower acute toxicities and an improved OS were observed in the reduction-cohort.
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http://dx.doi.org/10.1016/j.radonc.2019.07.028DOI Listing
February 2020

SBRT combined with concurrent chemoradiation in stage III NSCLC: Feasibility study of the phase I Hybrid trial.

Radiother Oncol 2020 01 17;142:224-229. Epub 2019 Aug 17.

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

Purpose: To assess the technical and clinical feasibility of the phase I Hybrid trial (NCT01933568), combining SBRT of the primary tumor (PT) and fractionated radiotherapy (FRT) to the lymph nodes (LN).

Materials And Methods: Ten patients with stage III NSCLC with a peripheral PT < 5 cm were prospectively selected. The EQD corrected normal tissue dose parameters of the FRT plan of 24×2.75 Gy to PT and 24×2.42 Gy to LN (IMRT) was compared with 3×18 Gy on the PT and 24×2.42 Gy on the LN (VMAT) using a Wilcoxon signed-rank test. To anticipate differential motion between PT and LN, worst-case scenarios for OAR were calculated. Electronic portal imaging device (EPID) dosimetry analysis was performed to rule out dosimetric errors during delivery.

Results: The Hybrid plans revealed a significant decrease of esophagus EUD n = 0.13, lung V5 and V20 and a significant increase in D of the PRV of the mediastinal envelope. Plans were robust against differential motion of 5 mm between PT and LN in 8 patients and failed in 2 patients due to spinal cord constraints. Average pass rates were ≥87% for EPID dosimetry.

Conclusions: SBRT and FRT could be combined within the given OAR constraints. Safety will be assessed in the Hybrid trial.
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http://dx.doi.org/10.1016/j.radonc.2019.07.015DOI Listing
January 2020

Estimation of the α/β ratio of non-small cell lung cancer treated with stereotactic body radiotherapy.

Radiother Oncol 2020 01 17;142:210-216. Epub 2019 Aug 17.

Department of Radiation Oncology, University Hospital Zurich, Switzerland.

Background: High-dose hypofractionated radiotherapy should theoretically result in a deviation from the typical linear-quadratic shape of the cell survival curve beyond a certain threshold dose, yet no evidence for this hypothesis has so far been found in clinical data of stereotactic body radiotherapy treatment (SBRT) for early-stage non-small cell lung cancer (NSCLC). A pragmatic explanation is a larger α/β ratio than the conventionally assumed 10 Gy. We here attempted an estimation of the α/β ratio for NSCLC treated with SBRT using individual patient data.

Materials And Methods: We combined two large retrospective datasets, yielding 1294 SBRTs (≤10 fractions) of early stage NSCLC. Cox proportional hazards regression, a logistic tumor control probability model and a biologically motivated Bayesian cure rate model were used to estimate the α/β ratio based on the observed number of local recurrences and accounting for tumor size.

Results: A total of 109 local progressions were observed after a median of 17.7 months (range 0.6-76.3 months). Cox regression, logistic regression of 3 year tumor control probability and the cure rate model yielded best-fit estimates of α/β = 12.8 Gy, 14.9 Gy and 12-16 Gy (depending on the prior for α/β), respectively, although with large uncertainties that did not rule out the conventional α/β = 10 Gy.

Conclusions: Clinicians can continue to use the simple LQ formalism to compare different SBRT treatment schedules for NSCLC. While α/β = 10 Gy is not ruled out by our data, larger values in the range 12-16 Gy are more probable, consistent with recent meta-regression analyses.
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http://dx.doi.org/10.1016/j.radonc.2019.07.008DOI Listing
January 2020

Consolidative thoracic radiotherapy in stage IV small cell lung cancer: Selection of patients amongst European IASLC and ESTRO experts.

Radiother Oncol 2019 06 15;135:74-77. Epub 2019 Mar 15.

Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.

Background: The role of consolidative thoracic radiotherapy (TRT) in stage IV small cell lung cancer (SCLC) is not uniformly accepted.

Methods: We obtained a list of 13 European medical oncologists from the International Association for the Study of Lung Cancer (IASLC) and 13 European radiation oncologists from the European Society for Therapeutic Radiation Oncology (ESTRO). The strategies in decision making for TRT in stage IV SCLC were collected. Decision trees were created representing these strategies. Frequencies of recommending TRT were analysed for various parameter combinations based on the objective consensus methodology.

Results: The factors associated with the recommendation for TRT included fitness of the patient, limited extrathoracic tumour burden, initial bulky thoracic disease and response to chemotherapy. The highest consensus for TRT was in fit patients with limited extrathoracic tumour burden and initial bulky disease with either a complete extrathoracic response or partial thoracic response (92% recommend TRT). For these patients the recommendations were the same for medical and radiation oncologists. In the setting of partial response (intra- and extra-thoracically) without initial bulky thoracic disease radiation oncologists were more likely to recommend TRT than medical oncologists. For unfit patients or for patients with poor overall response to chemotherapy, the majority did not recommend TRT.

Conclusion: European radiation and medical oncologists specializing in lung cancer recommend TRT in selected patients with stage IV SCLC and restrict its use primarily to fit patients who responded to chemotherapy with limited extrathoracic tumour burden.
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http://dx.doi.org/10.1016/j.radonc.2019.02.010DOI Listing
June 2019

Pre-hydration in cisplatin-based CCRT: Effects on tumour concentrations and treatment outcome.

Radiother Oncol 2019 05 31;134:30-36. Epub 2019 Jan 31.

Department of Nuclear Medicine, Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

Aims: Pre-hydration is routinely applied to reduce nephrotoxicity in concurrent cisplatin-based chemo-radiotherapy (CCRT). However, pre-hydration may also have systemic effects, potentially leading to lower tumour cisplatin concentrations. We investigated the impact of pre-hydration on tumour cisplatin concentrations in mice, and on treatment outcomes in a clinical cohort study.

Materials And Methods: Four groups of 20 mice received either no pre-hydration prior to full-dose (6 mg/kg) or half-dose cisplatin, overnight dehydration prior to full-dose cisplatin (dehydration), or NaCl intraperitoneally prior to full-dose cisplatin (pre-hydration). Kidney function and tumour platinum concentration were measured. In patients, a retrospective study compared 2 historical NSCLC cohorts which received CCRT with daily cisplatin, with and without standard pre-hydration. Overall survival (OS) and progression free survival (PFS) were compared using Kaplan-Meier and cox-regression.

Results: Pre-hydration significantly decreased cisplatin tumour concentrations in mice, comparable to mice receiving half the dose. In 419 patients (211 without and 208 with pre-hydration) with median follow-up 22 months, there were no significant differences in PFS (18 vs. 15 months) or OS (23 vs. 23 months).

Conclusion: Pre-hydration reduces cisplatin tumour concentrations in mice, but it does not compromise treatment outcomes in NSCLC patients treated with daily cisplatin and radiotherapy.
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http://dx.doi.org/10.1016/j.radonc.2019.01.015DOI Listing
May 2019

Prophylactic cranial irradiation in stage IV small cell lung cancer: Selection of patients amongst European IASLC and ESTRO experts.

Radiother Oncol 2019 04 31;133:163-166. Epub 2019 Jan 31.

Maastricht University Medical Center, Department of Radiation Oncology (Maastro Clinic), School for Oncology and Developmental Biology (GROW), the Netherlands.

Background: Due to conflicting results between major trials the role of prophylactic cranial irradiation (PCI) in stage IV small cell lung cancer (SCLC) is controversial.

Methods: We obtained a list of 13 European experts from both the European Society for Therapeutic Radiation Oncology (ESTRO) and the International Association for the Study of Lung Cancer (IASLC). The strategies in decision making for PCI in stage IV SCLC were collected. Decision trees were created representing these strategies. Analysis of consensus was performed with the objective consensus methodology.

Results: The factors associated with the recommendation for the use of PCI included the fitness of the patient, young age and good response to chemotherapy. PCI was recommended by the majority of experts for non-elderly fit patients who had at least a partial response (PR) to chemotherapy (for complete remission (CR) 85% of radiation oncologists and 69% of medical oncologists, for PR: 85% of radiation oncologists and 54% of medical oncologists). For patients with stable disease after chemotherapy, PCI was recommended by 6 out of 13 (46%) radiation oncologists and only 3 out of 13 medical oncologists (23%). For elderly fit patients with CR, a majority recommended PCI (62%) and no consensus was reached for patients with PR.

Conclusion: European radiation and medical oncologists specializing in lung cancer recommend PCI in selected patients and restrict its use primarily to fit, non-elderly patients who responded to chemotherapy.
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http://dx.doi.org/10.1016/j.radonc.2018.12.014DOI Listing
April 2019

Modeling radiation pneumonitis of pulmonary stereotactic body radiotherapy: The impact of a local dose-effect relationship for lung perfusion loss.

Radiother Oncol 2019 03 9;132:142-147. Epub 2019 Jan 9.

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

Purpose: To investigate if a local dose-effect (LDE) relationship for perfusion loss improves the NTCP model fit for SBRT induced radiation pneumonitis (RP) compared to conventional LDEs.

Methods And Materials: Multi-institutional data of 1015 patients treated with SBRT were analyzed. Dose distributions were converted to NTD with α/β = 3 Gy. The Lyman-Kutcher-Burman NTCP model was fitted to the incidence grade ≥2 RP by maximum likelihood estimation with mean lung dose (MLD), equivalent uniform doses (EUD) using three LDE functions (power-law (EUD), logistic with 2 free parameters (EUD) and logistic with fixed parameters describing local perfusion loss (EUD)) and volume above a threshold dose (V). Models were compared with the Akaike weights (Aw) derived from the Akaike information criteria (AIC).

Results: The median time to grade ≥2 RP was 4.2 months and plateaued after 17 months at 5.4%. A strong dose-effect relationship for RP incidence was observed. The EUD based NTCP model had the lowest AIC. The Aw were 0.53, 0.19, 0.11, 0.11, 0.05 for the EUD, V, MLD, EUD and EUD LDEs respectively.

Conclusion: A LDE for perfusion loss provided modest improvement in NTCP model fit for SBRT induced radiation pneumonitis.
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http://dx.doi.org/10.1016/j.radonc.2018.12.015DOI Listing
March 2019

Contact of a tumour with the pleura is not associated with regional recurrence following stereotactic ablative radiotherapy for early stage non-small cell lung cancer.

Radiother Oncol 2019 02 31;131:120-126. Epub 2018 Dec 31.

Department of Radiation Oncology (MAASTRO), GROW, School for Oncology and Developmental Biology, Maastricht University Medical Centre, the Netherlands; Institute of Radiooncology - OncoRay, Helmholtz Zentrum Dresden - Rossendorf, Dresden, Germany; OncoRay, National Center for Radiation Research in Oncology, Dresden, Germany; Department of Radiation Oncology, University Hospital Carl Gustav Carus of Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), Partnersite Dresden, Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background And Purpose: The aim was to investigate the incidence of isolated regional failure following stereotactic ablative radiotherapy (SABR) and risk factors for recurrence.

Materials And Methods: Early stage non-small cell lung cancer (NSCLC) patients treated with SABR were included in this retrospective cohort study, with isolated regional recurrence (IRR) as primary endpoint, distant recurrence (DR) and overall survival (OS) as secondary endpoints. Survival analyses were performed using the cumulative incidence function (IRR and DR) or the Kaplan-Meier method (OS) and Cox proportional hazards modelling for univariate and multivariate analyses. The prognostic effect of contact between the tumour and the pleura was investigated using the CT scans used for SABR planning.

Results: A total of 554 patients were included, of whom 494 could be analysed for IRR. The median follow-up for surviving patients was 48.1 months. Twenty-one patients developed an IRR (4%). The cumulative incidence of IRR and DR after 1-, 2-, and 5 years was 2%, 3%, 7% and 8%, 15% and 21%, respectively. Two year OS was 71%. The presence and type of pleural contact was not associated with any of the studied outcomes.

Conclusion: The presence, type and length of pleural contact as surrogate for visceral pleural invasion were not predictive for outcome. Further studies focussing on risk factors for occult nodal involvement, (I)RR, distant metastases and mortality in early stage NSCLC are warranted for the development of risk adapted diagnostic, treatment and follow-up strategies as more younger, operable and fitter patients receive SABR.
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http://dx.doi.org/10.1016/j.radonc.2018.11.024DOI Listing
February 2019
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