Publications by authors named "Barbara Stam"

13 Publications

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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

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

Quantification of Esophageal Tumor Motion and Investigation of Different Image-Guided Correction Strategies.

Pract Radiat Oncol 2020 Mar - Apr;10(2):84-92. Epub 2019 Nov 29.

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

Purpose: To accurately quantify esophageal tumor position variability and to optimize image guided correction strategies.

Material And Methods: Esophageal cancer patients receiving chemoradiotherapy (41.4-50.4 Gy in 23-28 fractions combined with carboplatin plus paclitaxel) were included in a prospective cohort study (NCT02139488). Gold fiducial markers were inserted into the esophageal tumors during diagnostic endoscopic ultrasound. Four-dimensional (4D) planning computed tomography (CT) and daily 4D cone beam (CB) CT scans were acquired. Each CBCT was registered to the planning CT using different regions of interest (bone; 3D), and carina, diaphragm, clinical target volume (CTV), and fiducial markers (4D) for alignment and using the fiducial markers as the true tumor position. Subsequently, a planning target volume (PTV) margin accounting for residual uncertainties, including the average respiratory motion, was calculated for each of these registrations.

Results: Fifty-six patients with tumors located in the proximal (n = 1), mid (n = 7), or distal esophagus (n = 25) or at the gastroesophageal junction (n = 23) were included. The average peak-to-peak respiratory tumor motion was 0.20, 0.92, and 0.34 cm on the planning CT in left-right (LR), cranial-caudal (CC), and anterior-posterior (AP) directions, respectively. The required PTV margin with average motion amplitude, depending on the correction strategy used for image guidance, ranged from 0.8 cm to 1.0 cm, 1.1 cm to 1.6 cm, and 0.7 cm to 0.9 cm in LR, CC, and AP direction, respectively. A registration based on the CTV resulted in the smallest PTV margins (0.8, 1.1, and 0.7 cm in LR, CC, and AP direction, respectively). For bone registration the calculated PTV margins were 1.0, 1.3, and 0.7 cm in LR, CC, and AP directions, respectively. The registration based on the diaphragm increased PTV margins.

Conclusions: Substantial and anisotropic position variability of esophageal tumors was observed during radiation therapy, and nonuniform margins should be considered. Cranial-caudal PTV margins need to be larger than those commonly used. Target positioning during image-guided radiotherapy could be improved with a CTV registration-based correction strategy.
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http://dx.doi.org/10.1016/j.prro.2019.11.012DOI Listing
October 2020

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

Subgroup Survival Analysis in Stage I-II NSCLC Patients With a Central Tumor Partly Treated With Risk-Adapted SBRT.

Int J Radiat Oncol Biol Phys 2019 01 31;103(1):132-141. Epub 2018 Aug 31.

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

Purpose: Stereotactic body radiation therapy has been associated with increased toxicity when delivered to patients with early-stage non-small cell lung cancer with a tumor within 2 cm of the proximal bronchial tree (PBT). We investigated noncancer deaths for these patients as related to gross tumor volume (GTV) proximity to the PBT, compared with peripheral tumors.

Methods And Materials: We included 765 patients with early-stage non-small cell lung cancer who were treated with stereotactic body radiation therapy to a median of 3 × 18 Gy. Central tumors were treated with a risk-adapted (less-intense) schedule (mostly 8 fractions) in 55% of the patients in the first-centimeter group and 27% of the patients in the second-centimeter group. An average anatomy with contouring of PBT and organs at risk (OARs) was deformed onto each patient to obtain the distance of the GTV to the PBT and doses to OARs. Log-rank, 1-way analysis of variance, and Cox regressions were performed to assess differences in the first-centimeter, second centimeter, and peripheral groups and associations with noncancer deaths.

Results: The median overall survival was 42.7 months, the median noncancer death occurred in 57.3 months, and the median follow-up was 34.8 months. Noncancer death in the first-centimeter group (31 patients) was significantly different from noncancer death in the other groups, with a hazard ratio of 3.175 (P < .001). Noncancer death in the second-centimeter group (71 patients) was not different from noncancer death in the peripheral group (P = .53). Doses to OARs were higher in the first- and second-centimeter groups than in the peripheral group for all OARs. High dose to the PBT was associated with noncancer death (D1%; hazard ratio, 1.006 Gy; P = .003).

Conclusions: Patients with a GTV in the first centimeter surrounding the PBT died more often from causes other than cancer compared with other patients. Noncancer death in patients with a GTV in the second centimeter, who partly received a risk-adapted schedule, was comparable to that in patients with a peripheral tumor.
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http://dx.doi.org/10.1016/j.ijrobp.2018.08.040DOI Listing
January 2019

Heart dose associated with overall survival in locally advanced NSCLC patients treated with hypofractionated chemoradiotherapy.

Radiother Oncol 2017 10 19;125(1):62-65. Epub 2017 Sep 19.

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

Association of heart dose and overall survival was investigated in a cohort including 469 locally-advanced NSCLC patients receiving daily low-dose hypofractionated chemo-radiotherapy. Significant associations were found over a range of dose parameters. Multivariate analysis showed significant associations of heart_V:HR=1.007% (95% CI:1.002-1.013; p=0.006), age:HR=1.026year (1.011-1.042; p=0.001) and GTV volume:HR=1.001cc (1.000-1.002; p=0.006) with overall survival.
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http://dx.doi.org/10.1016/j.radonc.2017.09.004DOI Listing
October 2017

Dose to heart substructures is associated with non-cancer death after SBRT in stage I-II NSCLC patients.

Radiother Oncol 2017 06 2;123(3):370-375. Epub 2017 May 2.

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

Background And Purpose: To investigate potential associations between dose to heart (sub)structures and non-cancer death, in early stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT).

Methods: 803 patients with early stage NSCLC received SBRT with predominant schedules of 3×18Gy (59%) or 4×12Gy (19%). All patients were registered to an average anatomy, their planned dose deformed accordingly, and dosimetric parameters for heart substructures were obtained. Multivariate Cox regression and a sensitivity analysis were used to identify doses to heart substructures or heart region with a significant association with non-cancer death respectively.

Results: Median follow-up was 34.8months. Two year Kaplan-Meier overall survival rate was 67%. Of the deceased patients, 26.8% died of cancer. Multivariate analysis showed that the maximum dose on the left atrium (median 6.5Gy EQD2, range=0.009-197, HR=1.005, p-value=0.035), and the dose to 90% of the superior vena cava (median 0.59Gy EQD2, range=0.003-70, HR=1.025, p-value=0.008) were significantly associated with non-cancer death. Sensitivity analysis identified the upper region of the heart (atria+vessels) to be significantly associated with non-cancer death.

Conclusions: Doses to mainly the upper region of the heart were significantly associated with non-cancer death. Consequently, dose sparing in particular of the upper region of the heart could potentially improve outcome, and should be further studied.
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http://dx.doi.org/10.1016/j.radonc.2017.04.017DOI Listing
June 2017

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

Radiother Oncol 2017 05 19;123(2):176-181. Epub 2017 Jan 19.

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

Background And Purpose: To determine a dose-effect relation for radiation induced rib fractures after stereotactic body radiation therapy (SBRT) in early stage non-small cell lung cancer (NSCLC). Automatic rib delineation has enabled the analysis of a large patient group.

Material And Methods: Four-hundred and sixty-six patients with stage I/II NSCLC received SBRT with a median of 54Gy in 3 fractions. The optimal EQD2-corrected dose parameter to predict (a)symptomatic fractures was found using Cox regression. Three normal tissue complication probability (NTCP) models based on this optimal parameter were constructed: (1) at a median follow up (FU) of 26months, (2) for all data, with time to toxicity taken into account and (3) at a FU of 26months, excluding low dose ribs.

Results: The median time to fracture was 22 (range 5-51) months. Maximum rib dose best predicted fractures. The TD (dose with 50% complication) of the second NTCP model was 375Gy. The TD was significantly higher for the other models indicating an under-estimation of the dose effect at the median follow-up time and/or when excluding low dose ribs.

Conclusions: The risk of symptomatic rib fractures after SBRT was significantly correlated to dose, and was <5% at 26months when D<225Gy.
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http://dx.doi.org/10.1016/j.radonc.2017.01.004DOI Listing
May 2017

Validation of automatic segmentation of ribs for NTCP modeling.

Radiother Oncol 2016 Mar 29;118(3):528-34. Epub 2015 Dec 29.

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

Background And Purpose: Determination of a dose-effect relation for rib fractures in a large patient group has been limited by the time consuming manual delineation of ribs. Automatic segmentation could facilitate such an analysis. We determine the accuracy of automatic rib segmentation in the context of normal tissue complication probability modeling (NTCP).

Materials And Methods: Forty-one patients with stage I/II non-small cell lung cancer treated with SBRT to 54 Gy in 3 fractions were selected. Using the 4DCT derived mid-ventilation planning CT, all ribs were manually contoured and automatically segmented. Accuracy of segmentation was assessed using volumetric, shape and dosimetric measures. Manual and automatic dosimetric parameters Dx and EUD were tested for equivalence using the Two One-Sided T-test (TOST), and assessed for agreement using Bland-Altman analysis. NTCP models based on manual and automatic segmentation were compared.

Results: Automatic segmentation was comparable with the manual delineation in radial direction, but larger near the costal cartilage and vertebrae. Manual and automatic Dx and EUD were significantly equivalent. The Bland-Altman analysis showed good agreement. The two NTCP models were very similar.

Conclusions: Automatic rib segmentation was significantly equivalent to manual delineation and can be used for NTCP modeling in a large patient group.
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http://dx.doi.org/10.1016/j.radonc.2015.12.014DOI Listing
March 2016

How the blood pool properties at onset affect the temporal behavior of simulated bruises.

Med Biol Eng Comput 2012 Feb 20;50(2):165-71. Epub 2012 Jan 20.

Biomedical Engineering and Physics, Academic Medical Centre, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands.

The influence of initial blood pool properties on the temporal behavior of bruises is currently unknown. We addressed this important issue by utilizing three typical classes of bruises in our three-layered finite compartment model. We simulated the effects of their initial shapes, regularity of boundaries and initial blood concentration distributions (gaussian vs. homogeneous) on the hemoglobin and bilirubin areas in the dermal top layer. Age determination of bruises with gaussian hemoglobin concentration was also addressed. We found that the initial blood pool properties strongly affect bruise behavior. We determined the age of a 200-h simulated bruise with gaussian hemoglobin concentration with 3 h uncertainty. In conclusion, bruise behavior depends non-intuitively on the initial blood pool properties; hence, a model that includes shape, area and concentration distribution at onset is indispensable. Future age determination, including inhomogeneous hemoglobin distributions, will likely be based on the presented method for gaussian distributions.
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http://dx.doi.org/10.1007/s11517-012-0860-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272227PMC
February 2012

Can color inhomogeneity of bruises be used to establish their age?

J Biophotonics 2011 Oct 19;4(10):759-67. Epub 2011 May 19.

Department of Biomedical Engineering and Physics, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Bruises become spatially inhomogeneous during the healing process; a smaller red-blue core area, caused by hemoglobin, is surrounded by a larger yellow area, caused by bilirubin, which is enzymatically formed from hemoglobin. These two areas develop at different rates and hence carry information about the age of the bruise. We present a proof of principle demonstration that the age of bruises can be determined via an inverse procedure using a mathematical model and daily measurements of these two areas using a hyperspectral imaging system. The inaccuracy found is 2.3% for fresh bruises and 3 to 24% for bruises up to 3 days old. In conclusion, color inhomogeneity of bruises can be used to determine their age. We expect that future age determination of bruises by the inverse procedure described here, possibly also including the distribution of concentrations in the areas will open up a new phase in clinical bruise classification.
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http://dx.doi.org/10.1002/jbio.201100021DOI Listing
October 2011

3D finite compartment modeling of formation and healing of bruises may identify methods for age determination of bruises.

Med Biol Eng Comput 2010 Sep 16;48(9):911-21. Epub 2010 Jun 16.

Biomedical Engineering and Physics, Academic Medical Centre, Amsterdam, The Netherlands.

Simulating the spatial and temporal behavior of bruises may identify methods that allow accurate age determination of bruises to assess child abuse. We developed a numerical 3D model to simulate the spatial kinetics of hemoglobin and bilirubin during the formation and healing of bruises. Using this model, we studied how skin thickness, bruise diameter and diffusivities affect the formation and healing of circular symmetric bruises and compared a simulated bruise with a natural inhomogeneous bruise. Healing is faster for smaller bruises in thinner and less dense skin. The simulated and natural bruises showed similar spatial and temporal dynamics. The different spatio-temporal dynamics of hemoglobin and bilirubin allows age determination of model bruises. Combining our model predictions with individual natural bruises may allow optimizing our model parameters. It may particularly identify methods for more accurate age determination than currently possible to aid the assessment of child abuse.
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http://dx.doi.org/10.1007/s11517-010-0647-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2926474PMC
September 2010

[Signalling and tackling child abuse].

Ned Tijdschr Geneeskd 2010 ;154:A1450

Academisch Medisch Centrum, Amsterdam, The Netherlands.

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June 2010