Role of minor salivary glands in developing patient-rated xerostomia and sticky saliva during day and night.

PURPOSE: The purpose of this prospective study was to investigate the relationship between xerostomia during the day (XERday) and night (XERnight) and sticky saliva during the day (STICday) and night (STICnight) and dose distributions in different major and minor salivary glands among head and neck cancer (HNC) patients treated with primary radiotherapy (RT) or chemoradiation (CHRT). METHODS AND MATERIALS: The study population was composed of 201 consecutive HNC patients treated with intensity modulated radiotherapy (IMRT) or 3-dimensional conformal radiotherapy (3D-CRT). All patients were included in a standard follow up programme in which acute and late side effects and quality of life (QoL) were prospectively assessed, prior to, during and after treatment. The primary endpoints were XERday, XERnight, STICday, STICnight as assessed by the Groningen Radiotherapy Induced Xerostomia questionnaire (GRIX) six months after completion of treatment. 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, buccal mucosa and lips. Patients with moderate-to-severe xerostomia or moderate-to-severe sticky saliva, respectively, at baseline were excluded. In order to determine which salivary glands were most important, a multivariate logistic regression analysis with an extended bootstrapping technique was used. RESULTS: In total, 29% and 19% of the cases suffered from XERday and XERnight, respectively. The multivariate analysis showed that baseline xerostomia and the mean parotid gland dose were the most important predictors for XERday and XERnight. At 6months after (CH)RT, 10% and 12% of the cases reported STICday and STICnight respectively. We were not able to identify prognostic factors related to dose distributions with regard to STICday. The mean submandibular gland dose was associated with STICnight. Baseline xerostomia and sticky saliva scores on the GRIX were associated with XERday, XERnight, STICday. Increasing age was correlated with both XERnight and STICnight. CONCLUSION: Organs at risk for XERday and STICday are similar to organs at risk for XERnight and STICnight.

External validation of three dimensional conformal radiotherapy based NTCP models for patient-rated xerostomia and sticky saliva among patients treated with intensity modulated radiotherapy.

PURPOSE: The purpose of this study was to investigate the ability of predictive models for patient-rated xerostomia (XER(6M)) and sticky saliva (STIC(6M)) at 6 months after completion of primary (chemo)radiation developed in head and neck cancer patients treated with 3D-conformal radiotherapy (3D-CRT) to predict outcome in patients treated with intensity modulated radiotherapy (IMRT). METHODS AND MATERIALS: Recently, we published the results of a prospective study on predictive models for patient-rated xerostomia and sticky saliva in head and neck cancer patients treated with 3D-CRT (3D-CRT based NTCP models). The 3D-CRT based model for XER(6M) consisted of three factors, including the mean parotid dose, age, and baseline xerostomia (none versus a bit). The 3D-CRT based model for STIC(6M) consisted of the mean submandibular dose, age, the mean sublingual dose, and baseline sticky saliva (none versus a bit). In the current study, a population consisting of 162 patients treated with IMRT was used to test the external validity of these 3D-CRT based models. External validity was described by the explained variation (R(2) Nagelkerke) and the Brier score. The discriminative abilities of the models were calculated using the area under the receiver operating curve (AUC) and calibration (i.e. the agreement between predicted and observed outcome) was assessed with the Hosmer-Lemeshow "goodness-of-fit" test. RESULTS: Overall model performance of the 3D-CRT based predictive models for XER(6M) and STIC(6M) was significantly worse in terms of the Brier score and R(2) Nagelkerke among patients treated with IMRT. Moreover the AUC for both 3D-CRT based models in the IMRT treated patients were markedly lower. The Hosmer-Lemeshow test showed a significant disagreement for both models between predicted risk and observed outcome. CONCLUSION: 3D-CRT based models for patient-rated xerostomia and sticky saliva among head and neck cancer patients treated with primary radiotherapy or chemoradiation turned out to be less valid for patients treated with IMRT. The main message from these findings is that models developed in a population treated with a specific technique cannot be generalised and extrapolated to a population treated with another technique without external validation.

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.

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.

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 Akaike's 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.