P. Doornaert

Impact of Late Treatment-Related Toxicity on Quality of Life Among Patients With Head and Neck Cancer Treated With Radiotherapy

PURPOSE To investigate the impact of treatment-related toxicity on health-related quality of life (HRQoL) among patients with head and neck squamous cell carcinoma treated with radiotherapy either alone or in combination with chemotherapy or surgery. PATIENTS AND METHODS The study sample was composed of 425 disease-free patients. Toxicity was scored according to the European Organisation for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group (RTOG) late radiation-induced morbidity scoring system. HRQoL was assessed using the EORTC Quality of Life Questionnaire C30. These assessments took place at 6, 12, 18, and 24 months after completion of radiotherapy. The analysis was performed using a multivariate analysis of variance. RESULTS Of the six RTOG scales investigated, two significantly affected self-reported HRQoL, salivary gland (RTOG(xerostomia)) and esophagus/pharynx (RTOG(swallowing)). Although RTOG(xerostomia) was reported most frequently, HRQoL was most affected by RTOG(swallowing), particularly in the first 18 months after completion of radiotherapy. CONCLUSION Late radiation-induced toxicity, particularly RTOG(swallowing) and RTOG(xerostomia), has a significant impact on the more general dimensions of HRQoL. These findings suggest that the development of new radiation-induced delivery techniques should not only focus on reduction of the dose to the salivary glands, but also on anatomic structures that are involved in swallowing.

Intensity-Modulated Radiotherapy Reduces Radiation-Induced Morbidity and Improves Health-Related Quality of Life: Results of A Nonrandomized Prospective Study Using A Standardized Follow-Up Program

PURPOSE The purpose of this study was to compare intensity-modulated radiation therapy (IMRT) and three-dimensional conventional radiotherapy (3D-CRT) with regard to patient-rated xerostomia, Radiation Therapy Oncology Group (RTOG) acute and late xerostomia and health-related quality of life (HRQoL) among patients with head and neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS Included were 241 patients with HNSCC treated with bilateral irradiation +/- chemotherapy. Since 2000, all patients treated with HNSCC were included in a program, which prospectively assessed acute and late morbidity according to the RTOG and HRQoL on a routine basis at regular intervals. Before October 2004, all patients were treated with 3D-CRT (N = 150). After clinical implementation in October 2004, 91 patients received IMRT. In this study, the differences regarding RTOG toxicity, xerostomia, and other items of HRQoL were analyzed. RESULTS The use of IMRT resulted in a significant reduction of the mean dose of the parotid glands (27 Gy vs. 43 Gy (p < 0.001). During radiation, Grade 2 RTOG xerostomia was significantly less with IMRT than with 3D-CRT. At 6 months, the prevalence of patient-rated moderate to severe xerostomia and Grade 2 or higher RTOG xerostomia was significantly lower after IMRT versus 3D-CRT. Treatment with IMRT also had a positive effect on several general and head and neck cancer-specific HRQoL dimensions. CONCLUSIONS IMRT results in a significant reduction of patient- and observer-rated xerostomia, as well as other head and neck symptoms, compared with standard 3D-CRT. These differences translate into a significant improvement of the more general dimensions of HRQoL.

A predictive model for swallowing dysfunction after curative radiotherapy in head and neck cancer

INTRODUCTION Recently, we found that swallowing dysfunction after curative (chemo) radiation (CH) RT has a strong negative impact on health-related quality of life (HRQoL), even more than xerostomia. The purpose of this study was to design a predictive model for swallowing dysfunction after curative radiotherapy or chemoradiation. MATERIALS AND METHODS A prospective study was performed including 529 patients with head and neck squamous cell carcinoma (HNSCC) treated with curative (CH) RT. In all patients, acute and late radiation-induced morbidity (RTOG Acute and Late Morbidity Scoring System) was scored prospectively. To design the model univariate and multivariate logistic regression analyses were carried out with grade 2 or higher RTOG swallowing dysfunction at 6 months as the primary (SWALL(6months)) endpoint. The model was validated by comparing the predicted and observed complication rates and by testing if the model also predicted acute dysphagia and late dysphagia at later time points (12, 18 and 24 months). RESULTS After univariate and multivariate logistic regression analyses, the following factors turned out to be independent prognostic factors for SWALL(6months): T3-T4, bilateral neck irradiation, weight loss prior to radiation, oropharyngeal and nasopharyngeal tumours, accelerated radiotherapy and concomitant chemoradiation. By summation of the regression coefficients derived from the multivariate model, the Total Dysphagia Risk Score (TDRS) could be calculated. In the logistic regression model, the TDRS was significantly associated with SWALL(6months) ((p<0.001). Subsequently, we defined three risk groups based on the TDRS. The rate of SWALL(6months) was 5%, 24% and 46% in case of low-, intermediate- and high-risk patients, respectively. These observed percentages were within the 95% confidence intervals of the predicted values. The TDRS risk group classification was also significantly associated with acute dysphagia (P<0.001 at all time points) and with late swallowing dysfunction at 12, 18 and 24 months (p<0.001 at all time points). CONCLUSION The TDRS is a simple and validated measure to predict swallowing dysfunction after curative (CH) RT for HNC. This classification system enables identification of patients who may benefit from strategies aiming at prevention of swallowing dysfunction after curative (CH) RT such as preventive swallowing exercises during treatment and/or emerging IMRT techniques aiming at sparing anatomical structures that are involved in swallowing.

Accelerated Radiotherapy With Carbogen and Nicotinamide for Laryngeal Cancer: Results of a Phase III Randomized Trial

PURPOSE To report the results from a randomized trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen inhalation and nicotinamide (ARCON) in laryngeal cancer. PATIENTS AND METHODS Patients with cT2-4 squamous cell laryngeal cancer were randomly assigned to AR (68 Gy within 36 to 38 days) or ARCON. To limit the risk of laryngeal necrosis, ARCON patients received 64 Gy on the laryngeal cartilage. The primary end point was local control. Secondary end points were regional control, larynx preservation, toxicity, disease-free survival, and overall survival. In a translational side study, the hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. RESULTS From April 2001 to February 2008, 345 patients were accrued. After a median follow-up of 44 months, local tumor control rate at 5 years was 78% for AR versus 79% for ARCON (P = .80), with larynx preservation rates of 84% and 87%, respectively (P = .48). The 5-year regional control was significantly better with ARCON (93%) compared with AR (86%, P = .04). The improvement in regional control was specifically observed in patients with hypoxic tumors and not in patients with well-oxygenated tumors (100% v 55%, respectively; P = .01). AR and ARCON produced equal levels of toxicity. CONCLUSION Despite lack of benefit in local tumor control for advanced laryngeal cancers, a significant gain in regional control rate, with equal levels of toxicity, was observed in favor of ARCON. The poor regional control of patients with hypoxic tumors is specifically countered by ARCON treatment.

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.

Risk-group definition by recursive partitioning analysis of patients with squamous cell head and neck carcinoma treated with surgery and postoperative radiotherapy

The objective of this study was to define different prognostic groups with regard to locoregional control (LRC) derived from recursive partitioning analysis (RPA).

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.

RapidArc planning and delivery in patients with locally advanced head-and-neck cancer undergoing chemoradiotherapy.

PURPOSE Volumetric modulated arc therapy (RapidArc, Varian Medical Systems) permits the delivery of highly conformal dose distributions. We studied planning and delivery in patients who underwent RapidArc for locally advanced head-and-neck cancer (HNC). METHODS AND MATERIALS A total of 35 consecutive patients who completed RapidArc with concurrent chemotherapy for Stages III-IV tumors of the oro- and hypopharynx/larynx in our center were identified. All underwent bilateral neck irradiation and 21 patients had at least N2 disease. A simultaneous integrated boost (SIB) delivered 70 Gy (in 2 Gy/fraction) to the planning target volume (PTV)(boost) and elective nodal regions (PTV(elect)) received 57.75 Gy. A standard planning constraint set was used and constraints for parotid glands were individually adapted. Treatments were delivered using two arcs after all plans were verified in a solid water phantom using GafChromic External Beam Therapy films. RESULTS RapidArc planning generally took 1.5-2 h, which was faster than with our previous seven-field intensity-modulated radiotherapy sliding window technique. Film dosimetry revealed that 0.6% of films exceeded a combination of dose differences ≥3% or distance to agreement ≥2 mm. More than 99% of both PTVs received ≥95% of the prescription dose. Average plan conformity index was 1.13 and mean dose to ipsilateral and contralateral parotid glands were 31.4 Gy and 26.1 Gy, respectively. The mean beam-on time was <3 min and mean number of monitor units was 426. CONCLUSIONS RapidArc achieved excellent target coverage and normal tissue sparing, with delivery completed in less than 3 min. RA is currently our standard intensity-modulated radiotherapy approach for advanced HNC.

Postoperative radiotherapy in squamous cell carcinoma of the oral cavity: The importance of the overall treatment time

PURPOSE To test the hypothesis that (1) the distinction between intermediate- and high-risk patients by clustering different prognostic factors results in a significant difference in treatment outcome and (2) a shorter interval between surgery and radiotherapy and shorter overall treatment times of radiation (OTTRT) result in higher rates of locoregional control (LRC). METHODS AND MATERIALS Included were patients (n = 217) with previously untreated squamous cell carcinoma of the oral cavity treated with radical surgery and postoperative radiotherapy. Patients with extranodal spread or microscopic residual disease and patients with two or more other risk factors (i.e., N2b-N3, >1 nodal level involved, perineural growth, or stage T3-T4) were classified as high-risk patients. Patients with only one other risk factor were classified as intermediate risk. RESULTS In the intermediate-risk group, the 3-year LRC was 87% as compared with 66% in the high-risk group (p = 0.0005). No association was found between interval and LRC. However, the OTTRT was significantly associated with LRC. The 3-year LRC was 87%, 75%, 69%, and 51% when the OTT was <6 weeks, 6-7 weeks, 7-8 weeks, and >8 weeks, respectively (p = 0.0004). The 3-year overall survival (OS) in the intermediate risk patients was 74% compared with 50% in the high-risk group (p = 0.0014). A significant association was also found between the OS and OTTRT. The OS increased from 50% when the OTTRT was >8 weeks to 74% when the OTT was <6 weeks (p = 0.006). Similar results were found with regard to the disease-free survival (DFS). In the multivariate analysis, both risk group and OTT were significantly associated with LRC, DFS, and OS. No significant interaction term was present between these two factors, which means that the OTT was of importance both for the high-risk and the intermediate-risk patients. CONCLUSION In the subset of patients with carcinoma of the oral cavity, the classification of high- and intermediate-risk patients by clustering a number of prognostic factors provides important prognostic information regarding LRC, DFS, and OS. The OTT was the most important prognostic factor both in the high-risk and intermediate-risk patients. Reducing the OTT to 6 weeks or less is a rather simple measure to achieve a considerable improvement of the outcome of treatment in this category of patients.

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.