Cornelis Schilstra

Predictive modelling for swallowing dysfunction after primary (chemo)radiation: Results of a prospective observational study

BACKGROUND AND PURPOSE The purpose of this large multicentre prospective cohort study was to identify which dose volume histogram parameters and pre-treatment factors are most important to predict physician-rated and patient-rated radiation-induced swallowing dysfunction (RISD) in order to develop predictive models for RISD after curative (chemo) radiotherapy ((CH) RT). MATERIAL AND METHODS The study population consisted of 354 consecutive head and neck cancer patients treated with (CH) RT. The primary endpoint was grade 2 or more swallowing dysfunction according to the RTOG/EORTC late radiation morbidity scoring criteria at 6 months after (CH) RT. The secondary endpoints were patient-rated swallowing complaints as assessed with the EORTC QLQ-H&N35 questionnaire. To select the most predictive variables a multivariate logistic regression analysis with bootstrapping was used. RESULTS At 6 months after (CH) RT the bootstrapping procedure revealed that a model based on the mean dose to the superior pharyngeal constrictor muscle (PCM) and mean dose to the supraglottic larynx was most predictive. For the secondary endpoints different predictive models were found: for problems with swallowing liquids the most predictive factors were the mean dose to the supraglottic larynx and radiation technique (3D-CRT versus IMRT). For problems with swallowing soft food the mean dose to the middle PCM, age (18-65 versus >65 years), tumour site (naso/oropharynx versus other sites) and radiation technique (3D-CRT versus IMRT) were the most predictive factors. For problems with swallowing solid food the most predictive factors were the mean dose to the superior PCM, the mean dose to the supraglottic larynx and age (18-65 versus >65 years). And for choking when swallowing the V60 of the oesophageal inlet muscle and the mean dose to the supraglottic larynx were the most predictive factors. CONCLUSIONS Physician-rated and patient-rated RISD in head and neck cancer patients treated with (CH) RT cannot be predicted with univariate relationships between the dose distribution in a single organ at risk and an endpoint. Separate predictive models are needed for different endpoints and factors other than dose volume histogram parameters are important as well.

Stabilizing gaze in flying blowflies

When the gaze is moved quickly, vision becomes blurred and the way in which three-dimensional structures are seen can be affected. How can these effects be minimized? During flight, blowflies (Calliphora vicina) turn both the head and the thorax very quickly, producing gaze shifts which affect vision. Here we show that blowflies reduce the effects of thorax movements on vision by moving the head later, and more quickly, than the thorax. This reduces the time in which gaze is shifting relative to the surroundings, and maximizes the time available for analysing the surroundings.

NTCP models for patient-rated xerostomia and sticky saliva after treatment with intensity modulated radiotherapy for head and neck cancer: The role of dosimetric and clinical factors

PURPOSE The purpose of this multicentre prospective study was to develop multivariable logistic regression models to make valid predictions about the risk of moderate-to-severe patient-rated xerostomia (XER(M6)) and sticky saliva 6 months (STIC(M6)) after primary treatment with intensity modulated radiotherapy (IMRT) with or without chemotherapy for head and neck cancer (HNC). METHODS AND MATERIALS The study population was composed of 178 consecutive HNC patients treated with IMRT. All patients were included in a standard follow up programme in which acute and late side effects and quality of life were prospectively assessed, prior to, during and after treatment. The primary endpoints were XER(M6) and STIC(M6) as assessed by the EORTC QLQ-H&N35 after completing IMRT. Organs at risk (OARs) potentially involved in salivary function were delineated on planning-CT, including the parotid, submandibular and sublingual glands and the minor glands in the soft palate, cheeks and lips. Patients with moderate-to-severe xerostomia or sticky saliva, respectively, at baseline were excluded. The optimal number of variables for a multivariate logistic regression model was determined using a bootstrapping method. RESULTS Eventually, 51.6% of the cases suffered from XER(M6). The multivariate analysis showed that the mean contralateral parotid gland dose and baseline xerostomia (none vs. a bit) were the most important predictors for XER(M6). For the multivariate NTCP model, the area under the receiver operating curve (AUC) was 0.68 (95% CI 0.60-0.76) and the discrimination slope was 0.10, respectively. Calibration was good with a calibration slope of 1.0. At 6 months after IMRT, 35.6% of the cases reported STIC(M6). The mean contralateral submandibular gland dose, the mean sublingual dose and the mean dose to the minor salivary glands located in the soft palate were most predictive for STIC(M6). For this model, the AUC was 0.70 (95% CI 0.61-0.78) and the discrimination slope was 0.12. Calibration was good with a calibration slope of 1.0. CONCLUSIONS The multivariable NTCP models presented in this paper can be used to predict patient-rated xerostomia and sticky saliva. The dose volume parameters included in the models can be used to further optimise IMRT treatment.

The Potential Benefit of Radiotherapy with Protons in Head and Neck Cancer with Respect to Normal Tissue Sparing: A Systematic Review of Literature

PURPOSE Clinical studies concerning head and neck cancer patients treated with protons reporting on radiation-induced side effects are scarce. Therefore, we reviewed the literature regarding the potential benefits of protons compared with the currently used photons in terms of lower doses to normal tissue and the potential for fewer subsequent radiation-induced side effects, with the main focus on in silico planning comparative (ISPC) studies. MATERIALS AND METHODS A literature search was performed by two independent researchers on ISPC studies that included proton-based and photon-based irradiation techniques. RESULTS Initially, 877 papers were retrieved and 14 relevant and eligible ISPC studies were identified and included in this review. Four studies included paranasal sinus cancer cases, three included nasopharyngeal cancer cases, and seven included oropharyngeal, hypopharyngeal, and/or laryngeal cancer cases. Seven studies compared the most sophisticated photon and proton techniques: intensity-modulated photon therapy versus intensity-modulated proton therapy (IMPT). Four studies compared different proton techniques. All studies showed that protons had a lower normal tissue dose, while keeping similar or better target coverage. Two studies found that these lower doses theoretically translated into a significantly lower incidence of salivary dysfunction. CONCLUSION The results of ISPC studies indicate that protons have the potential for a significantly lower normal tissue dose, while keeping similar or better target coverage. Scanned IMPT probably offers the most advantage and will allow for a substantially lower probability of radiation-induced side effects. The results of these ISPC studies should be confirmed in properly designed clinical trials.

POTENTIAL BENEFITS OF SCANNED INTENSITY-MODULATED PROTON THERAPY VERSUS ADVANCED PHOTON THERAPY WITH REGARD TO SPARING OF THE SALIVARY GLANDS IN OROPHARYNGEAL CANCER

PURPOSE To test the hypothesis that scanned intensity-modulated proton therapy (IMPT) results in a significant dose reduction to the parotid and submandibular glands as compared with intensity-modulated radiotherapy with photons (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) for oropharyngeal cancer. In addition, we investigated whether the achieved dose reductions would theoretically translate into a reduction of salivary dysfunction and xerostomia. METHODS AND MATERIALS Ten patients with N0 oropharyngeal carcinoma were used. The intensity-modulated plans delivered simultaneously 70 Gy to the boost planning target volume (PTV2) and 54 Gy to the elective nodal areas (PTV1). The 3D-CRT technique delivered sequentially 70 Gy and 46 Gy to PTV2 and PTV1, respectively. Normal tissue complication probabilities were calculated for salivary dysfunction and xerostomia. RESULTS Planning target volume coverage results were similar for IMPT and IMRT. Intensity-modulated proton therapy clearly improved the conformity. The 3D-CRT results were inferior to these results. The mean dose to the parotid glands by 3D-CRT (50.8 Gy), IMRT (25.5 Gy), and IMPT (16.8 Gy) differed significantly. For the submandibular glands no significant differences between IMRT and IMPT were found. The dose reductions obtained with IMPT theoretically translated into a significant reduction in normal tissue complication probability. CONCLUSION Compared with IMRT and 3D-CRT, IMPT improved sparing of the organs at risk, while keeping similar target coverage results. The dose reductions obtained with IMPT vs. IMRT and 3D-CRT varied widely per individual patient. Intensity-modulated proton therapy theoretically translated into a clinical benefit for most cases, but this requires clinical validation.

Calculation of the uncertainty in complication probability for various dose-response models, applied to the parotid gland

PURPOSE Usually, models that predict normal tissue complication probability (NTCP) are fitted to clinical data with the maximum likelihood (ML) method. This method inevitably causes a loss of information contained in the data. In this study, an alternative method is investigated that calculates the parameter probability distribution (PD), and, thus, conserves all information. The PD method also allows the calculation of the uncertainty in the NTCP, which is an (often-neglected) prerequisite for the intercomparison of both treatment plans and NTCP models. The PD and ML methods are applied to parotid gland data, and the results are compared. METHODS AND MATERIALS The drop in salivary flow due to radiotherapy was measured in 25 parotid glands of 15 patients. Together with the parotid gland dose-volume histograms (DVH), this enabled the calculation of the parameter PDs for three different NTCP models (Lyman, relative seriality, and critical volume). From these PDs, the NTCP and its uncertainty could be calculated for arbitrary parotid gland DVHs. ML parameters and resulting NTCP values were calculated also. RESULTS All models fitted equally well. The parameter PDs turned out to have nonnormal shapes and long tails. The NTCP predictions of the ML and PD method usually differed considerably, depending on the NTCP model and the nature of irradiation. NTCP curves and ML parameters suggested a highly parallel organization of the parotid gland. CONCLUSIONS Considering the substantial differences between the NTCP predictions of the ML and PD method, the use of the PD method is preferred, because this is the only method that takes all information contained in the clinical data into account. Furthermore, PD method gives a true measure of the uncertainty in the NTCP.

Development of NTCP models for head and neck cancer patients treated with three-dimensional conformal radiotherapy for xerostomia and sticky saliva : The role of dosimetric and clinical factors

PURPOSE The purpose of this multicentre prospective study was to investigate the significance of the radiation dose in the major and minor salivary glands, and other pre-treatment and treatment factors, with regard to the development of patient-rated xerostomia and sticky saliva among head and neck cancer (HNC) patients treated with primary (chemo-) radiotherapy ((CH)RT). METHODS AND MATERIALS The study population was composed of 167 consecutive HNC patients treated with three-dimensional conformal (3D-CRT) (CH) RT. The primary endpoint was moderate to severe xerostomia (XER6m) as assessed by the EORTC QLQ-H&N35 at 6 months after completing (CH)RT. The secondary endpoint was moderate to severe sticky saliva at 6 months (STIC6m). All organs at risk (OARs) potentially involved in salivary function were delineated on planning-CT, including the parotid, submandibular and sublingual glands and the minor glands in the soft palate, cheeks and lips. Patients with moderate to severe xerostomia or sticky saliva at baseline were excluded. The optimum number of variables for a multivariate logistic regression model was determined using a bootstrapping method. RESULTS The multivariate analysis showed the mean parotid dose, age and baseline xerostomia (none versus a bit) to be the most important predictors for XER6m. The risk of developing xerostomia increased with age and was higher when minor baseline xerostomia was present in comparison with patients without any xerostomia complaints at baseline. Model performance was good with an area under the curve (AUC) of 0.82. For STIC6m, the mean submandibular dose, age, the mean sublingual dose and baseline sticky saliva (none versus a bit) were most predictive for sticky saliva. The risk of developing STIC6m increased with age and was higher when minor baseline sticky saliva was present in comparison with patients without any sticky saliva complaints at baseline. Model performance was good with an AUC of 0.84. CONCLUSIONS Dose distributions in the minor salivary glands in patients receiving 3D-CRT have limited significance with regard to patient-rated symptoms related to salivary dysfunction. Besides the parotid and submandibular glands, only the sublingual glands were significantly associated with sticky saliva. In addition, reliable risk estimation also requires information from other factors such as age and baseline subjective scores. When these selected factors are included in predictive models, instead of only dose volume histogram parameters, model performance can be improved significantly.

A COMPARISON OF DOSE-RESPONSE MODELS FOR THE PAROTID GLAND IN A LARGE GROUP OF HEAD-AND-NECK CANCER PATIENTS

PURPOSE The dose-response relationship of the parotid gland has been described most frequently using the Lyman-Kutcher-Burman model. However, various other normal tissue complication probability (NTCP) models exist. We evaluated in a large group of patients the value of six NTCP models that describe the parotid gland dose response 1 year after radiotherapy. METHODS AND MATERIALS A total of 347 patients with head-and-neck tumors were included in this prospective parotid gland dose-response study. The patients were treated with either conventional radiotherapy or intensity-modulated radiotherapy. Dose-volume histograms for the parotid glands were derived from three-dimensional dose calculations using computed tomography scans. Stimulated salivary flow rates were measured before and 1 year after radiotherapy. A threshold of 25% of the pretreatment flow rate was used to define a complication. The evaluated models included the Lyman-Kutcher-Burman model, the mean dose model, the relative seriality model, the critical volume model, the parallel functional subunit model, and the dose-threshold model. The goodness of fit (GOF) was determined by the deviance and a Monte Carlo hypothesis test. Ranking of the models was based on Akaikes information criterion (AIC). RESULTS None of the models was rejected based on the evaluation of the GOF. The mean dose model was ranked as the best model based on the AIC. The TD(50) in these models was approximately 39 Gy. CONCLUSIONS The mean dose model was preferred for describing the dose-response relationship of the parotid gland.

The potential of intensity-modulated proton radiotherapy to reduce swallowing dysfunction in the treatment of head and neck cancer: A planning comparative study.

Abstract Background. Predictive models for swallowing dysfunction were developed previously and showed the potential of improved intensity-modulated radiotherapy to reduce the risk of swallowing dysfunction. Still the risk is high. The aim of this study was to determine the potential of swallowing-sparing (SW) intensity-modulated proton therapy (IMPT) in head and neck cancer (HNC) for reducing the risk of swallowing dysfunction relative to currently used photon therapy. Material and methods. Twenty-five patients with oropharyngeal (n = 21) and hypopharyngeal (n = 4) cancer received primary radiotherapy, including bilateral neck irradiation, using standard (ST) intensity-modulated photon therapy (IMRT). Prophylactic (54 Gy) and therapeutic (70 Gy) target volumes were defined. The dose to the parotid and submandibular glands was reduced as much as possible. Four additional radiotherapy plans were created for each patient: SW-IMRT, ST-IMPT, 3-beam SW-IMPT (3B-SW-IMPT) and 7-beam SW-IMPT (7B-SW-IMPT). All plans were optimized similarly, with additional attempts to spare the swallowing organs at risk (SWOARs) in the SW plans. Probabilities of swallowing dysfunction were calculated with recently developed predictive models. Results. All plans complied with standard HNC radiotherapy objectives. The mean parotid gland doses were similar for the ST and SW photon plans, but clearly lower in all IMPT plans (ipsilateral parotid gland ST-IMRT: 46 Gy, 7B-SW-IMPT: 29 Gy). The mean dose in the SWOARs was lowest with SW-IMPT, in particular with 7B-SW-IMPT (supraglottic larynx ST-IMRT: 60 Gy, 7B-SW-IMPT: 40 Gy). The observed dose reductions to the SWOARs translated into substantial overall reductions in normal tissue complication risks for different swallowing dysfunction endpoints. Compared with ST-IMRT, the risk of physician-rated grade 2–4 swallowing dysfunction was reduced on average by 8.8% (95% CI 6.5–11.1%) with SW-IMRT, and by 17.2% (95% CI: 12.7–21.7%) with 7B-SW-IMPT. Conclusion. SWOAR-sparing with proton therapy has the potential to substantially reduce the risk of swallowing dysfunction compared to similar treatment with photons.

The potential benefit of swallowing sparing intensity modulated radiotherapy to reduce swallowing dysfunction: An in silico planning comparative study

PURPOSE To apply recently developed predictive models for swallowing dysfunction to compare the predicted probabilities of swallowing dysfunction for standard intensity modulated radiotherapy (ST-IMRT) and swallowing sparing IMRT (SW-IMRT). MATERIALS AND METHODS Thirty head and neck cancer patients who previously underwent radiotherapy for the bilateral neck were selected for this study. For each patient, ST-IMRT and SW-IMRT simultaneous integrated boost treatment plans were created. ST-IMRT treatment plan optimisation aimed at obtaining adequate target volume coverage and sparing of the parotid and submandibular glands as much as possible. Objectives for SW-IMRT were similar, with additional objectives to spare the organs at risk related to swallowing dysfunction (SWOARs). Dose-volume data with ST-IMRT and SW-IMRT and normal tissue complication probabilities for physician-rated and patient-rated swallowing dysfunction were calculated with recently developed predictive models. RESULTS All plans had adequate target volume coverage and dose to critical organs was within accepted limits. Sparing of parotid glands was similar for ST-IMRT and SW-IMRT. With SW-IMRT, the mean dose to the various SWOARs was reduced. Absolute dose values and dose reductions with SW-IMRT differed per patient and per SWOAR and depended on N stage and tumour location. The mean reduction in predicted physician-rated Radiation Therapy Oncology Group (RTOG) grade 2-4 swallowing dysfunction was 9% (range, 3-20%). Mean reductions of the probability of patient-rated moderate to severe complaints with regard to the swallowing of solid food, soft food, liquid food and choking when swallowing were 8%, 2%, 1% and 1%, respectively. CONCLUSIONS New predictive models for swallowing dysfunction were applied to show potential reductions in physician and patient-rated swallowing dysfunction with IMRT that was specifically optimised to spare SWOARs.